疾患詳細

疾患詳細



円板状ループス発疹 (新生児) (Copyright Center for Birth Defects Information Services, Inc.)
(Kelly TE et al. Chondrodysplasia punctata stemming from maternal lupus erythematosus. Am. J. Med. Genet. 83: 397-401, 1999)

#152700
Lupus erythematosus, systemic (SLE)
(Excess lymphocyte low-molecular-weight DNA, included)
(Excess LMW-DNA, included)
[Arrhythmia, from maternal autoimmune disease, congenital]

紅斑性狼瘡, 全身性 (SLE)
(過剰なリンパ球低分子量DNA)
[不整脈, 先天性母自己免疫疾患性]
指定難病49 全身性エリテマトーデス
<小児慢性特定疾病 膠2 全身性エリテマトーデス>

遺伝子座:
1p13.2 {Systemic lupus erythematosus susceptibility to} 152700; PTPN22 600716
1q23 {Lupus erythematosus, systemic, susceptibility} 152700; FCGR3A 146740
1q23 {Systemic lupus erythematosus, susceptibility to} 152700; FCGR2B 604590
1q23 {Systemic lupus erythematosus, susceptibility} 152700; TNFSF6 134638
3p21.31 {Systemic lupus erythematosus, susceptibility to} 152700; TREX1 606609
4p16-p15.2 {Systemic lupus erythematosus, susceptibility to, 3} 152700; SLEB3 605480
4q24 {Systemic lupus erythematosus, association with} 152700; BANK1 610292
6p21.3 {Systemic lupus erythematosus, susceptibility to or protection against} 152700; C4A 120810
11q14 {Systemic lupus erythematosus with hemolytic anemia} 152700; SLEH1 607279
16p13.3 {Systemic lupus erythematosus, susceptibility to} 152700; DNASE1 125505
責任遺伝子:
 146790 Fc fragment of IgG, low affinity IIa, receptor for (FCG2)
 125505 Deoxyribonuclease I (DNASE1)
 600716 Protein-tyrosine phosphatase, nonreceptor-type 22 (PTPN22)
 134638 Tumor necrosis factor ligand superfamily, member 6 (TNFSF6)
 604590 Fc fragment of IgG, low affinity IIb, receptor for (FCGR2B)
遺伝形式:常染色体優性

(症状)
(GARD)

 Antinuclear antibody positivity (抗核抗体陽性) [HP:0003493] [2203]
 Antiphospholipid antibody positivity (抗リン脂質自己抗体陽性) [HP:0003613] [2203]
 Arthritis (関節炎) [HP:0001369] [15115]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Cutaneous photosensitivity (皮膚光線過敏症) [HP:0000992] [18028]
 Hemolytic anemia (溶血性貧血) [HP:0001878] [2202]
 Leukopenia (白血球減少) [HP:0001882] [2210]
 Malar rash (頬部発疹) [HP:0025300] [18007]
 Nephritis (腎炎) [HP:0000123] [0196]
 Pericarditis (心外膜炎) [HP:0001701] [1122]
 Pleuritis (胸膜炎) [HP:0002102]
 Psychosis (精神病) [HP:0000709] [0206]
 Seizures (けいれん) [HP:0001250] [01405]
 Systemic lupus erythematosus (SLE) [HP:0002725] [2203]
 Thrombocytopenia (血小板減少) [HP:0001873] [2218]

(UR-DBMS)
【一般】*けいれん
 *腎炎
【神経】*精神病
【胸郭】*胸膜炎
【心】*心外膜炎
【四肢】*関節炎
【皮膚】*紅斑性頬部発疹 出生時または生後1週間の間)
 *光線過敏症
 *円板状発疹
【検査】*抗リン脂質抗体
 *抗 dsDNA 抗体
 *血清抗核抗体
【血液】*白血球減少
 *血小板減少
 *溶血性貧血
 (母由来の抗-Ro/SS-A と抗-La/SS-B抗体を伴う新生児ヘモクロマトーシス) (周生期ヘモクロマトーシスまたは新生児鉄蓄積病)
【その他】補体欠損症 (例. C2 および C4 null アレル) がSLE を生じやすい
 LA class II アレルと自己抗体との連関あり
 16-55歳で発症
 女男比は 8:1 から 13:1

【一般】*胎児性徐脈
 *新生児不整脈
 *完全心ブロック (恒久性)
 浮腫
 全身浮腫
 呼吸窮迫症候群
 心不全
【心】心拡大
【X線】点状軟骨異形成

<小児慢性特定疾病 膠2 全身性エリテマトーデス>
診断方法
1. 頬部紅斑:鼻唇溝を避けた,頬骨隆起部の平坦あるいは隆起性の固定した紅斑
2. 円板状紅斑:付着する角化性落屑および毛嚢栓塞を伴う隆起性紅斑で,陳旧性病変では萎縮性瘢痕形成がみられることがある
3. 光線過敏症:日光に対する異常な反応の結果生じた皮疹が患者の病歴あるいは医師の観察により確認されたもの
4. 口腔潰瘍:口腔もしくは鼻咽腔潰瘍が医師により確認されたもの。通常は無痛性。
5. 関節炎:圧痛,腫脹あるいは関節液貯留により特徴づけられる,2か所あるいはそれ以上の末梢関節を侵す非びらん性関節炎
6. 漿膜炎(aかb):
 a)胸膜炎―胸膜炎によると考えられる疼痛, 医師による摩擦音の聴取, あるいは胸水,
 b)心膜炎―心電図, 摩擦音, あるいは心嚢液貯留により確認されたもの
7. 神経障害(a~fのいずれか):
 a)痙攣―有害な薬物もしくは既知の代謝異常, たとえば尿毒症, ケトアシドーシスあるいは電解質不均衡などが存在しないこと,
 b)精神障害―有害な薬物あるいは既知の代謝異常, たとえば尿毒症, ケトアシドーシスもしくは電解質不均衡などが存在しないこと,
 c)器質脳症候群Organic brain syndrome(失見当識, 記憶障害など),
 d)脳神経障害,
 e)頭痛, ,br> f)脳血管障害
注)いずれもSLE以外の原因を十分に鑑別すること
8. 腎障害(aかb):a)0.5g/日以上,あるいは定量試験を行わなかった場合は3+以上の持続性蛋白尿, b)細胞性円柱―赤血球, ヘモグロビン, 顆粒, 尿細管性円柱, あるいはそれらの混在
9. 血液学的異常 (a~d)のいずれか:
 a)溶血性貧血―網状赤血球増加を伴うもの,
 b)白血球減少症― 2 回あるいはそれ以上の測定時に4,000/mm3 未満であること,
 c)リンパ球減少症― 2 回あるいはそれ以上の測定時に1,500/mm3 未満であること,
 d)血小板減少症― 有害な薬物の投与なしに100,000/mm3 未満であること
10. 免疫学的異常 (a~c)のいずれか:
 a)抗dsDNA 抗体(native DNA に対する抗体)の異常高値,
 b)抗Sm 抗体(Sm 核抗原に対する抗体)の存在,
 c)抗リン脂質抗体陽性[ 1)IgG またはIgM 抗カルジオリピン抗体陽性, 2]標準的検査方法を用いたループス抗凝固因子陽性, 3)血清梅毒反応の生物学的偽陽性。少なくとも6 ヵ月間陽性で, 梅毒トレポネーマ運動抑制試験(TPI)あるいは梅毒トレポネーマ蛍光抗体吸収試験(FTA-ABS)により確認されたもの。
11. 免疫蛍光抗体法あるいはそれと等価の方法で,異常高値を示す抗核抗体を検出すること。経過中のどの時点でもよい。薬剤誘発性ループス症候群と関連することが知られる薬剤投与のないこと。
12. 血清補体(CH50またはC3のいずれか)の低下
 *経過観察中,経時的あるいは同時に,12 項目のうちいずれかの4 項目,あるいはそれ以上が存在するとき, 小児SLEの可能性が高い。
当該事業における対象基準
治療で非ステロイド系抗炎症薬, ステロイド薬, 免疫調整薬, 免疫抑制薬, 抗凝固療法, γグロブリン製剤, 強心利尿薬, 理学作業療法, 生物学的製剤又は血漿交換療法のうち一つ以上を用いている場合

概念・定義
 全身性エリテマトーデスsystemic lupus erythematosus (SLE)は, 紅斑性狼瘡(こうはんせいろうそう)lupus erythematosusとよばれる皮疹を特徴とし, 発熱や倦怠感などの全身症状を伴う全身性炎症性疾患である。自己免疫性疾患の一つであり, 抗DNA抗体などの自己抗体からなる免疫複合体が血管に沈着し, 補体系を活性化して血管や組織を傷害することで, 皮膚(皮疹), 腎臓(ループス腎炎), 中枢神経系(CNSループス)などに多彩な臓器病変を引き起こす。
 小児SLEとは16歳未満に発症したものをさすが, 成人例と比べて一般に経過は急性で重症例が多い。
疫学
 小児SLEは, SLE全体の15-17%を占める。本邦で実施された全国調査(1995年)1)では3,129例の小児リウマチ性疾患患者が登録され, SLEはその29%を占め, 若年性特発性関節炎に次いで多い疾患である。
 有病率は小児人口10万人当たり3.9~4.72)であり, 成人SLEの有病率(6.6~8.5 )と比較しても, それほど稀な疾患ではない。またその発病率は, 欧米では小児10万人当たり年間0.7~0.9例と報告されている。
 男女比は1:5.5であり3), 成人例(1:10~12)と比べると小児SLEでは相対的に男児の比率が高い。発症年齢は10歳以降が多いが, 7~8歳頃から発症する例もみられる。
病因
 双生児におけるSLE発症の一致率は, 一卵性の場合は25~30%, 二卵性の場合は5~10%であることから, 遺伝的要因を背景に, ウイルス感染, 性ホルモン, 紫外線, 薬物などの環境要因が加わることで発症すると考えられている。また最近では, 死滅した自己細胞から遊離したDNAやRNAの処理を担う自然免疫系に異常があり, そのことが自己抗体を産生させることが判明し, 自己免疫疾患の発症機序に自然免疫が関与することが注目されている
症状
1.臨床症状
1)皮膚・粘膜症状
 蝶形紅斑 (80%)は本症に特徴的であり, 発症早期から出現するため, しばしば診断の契機となる。初めは頬部の不定形の隆起性の紅斑で始まり, 紅斑は次第に癒合して拡大し, 両側頬部の紅斑が鼻根部をまたいで繋がると蝶形紅斑となる。
円盤状紅斑は円形のディスク(レコード盤)様の丘疹で, 経過とともに中心部は色素脱失して瘢痕化する。その他, 日光過敏やレイノー症状もみられる。
口内炎が上口蓋にみられることがあるが, 無痛性であるため気づかれていないことが多い。
2)腎炎
 初診時の50%, 全経過で60%に腎炎を発症するが, 尿異常があっても通常は無症状である。浮腫や学校検尿で気づかれる場合もある。
3)神経/精神症状
 痙攣や意識障害などの神経症状や, 精神症状が約20%にみられる。頭痛も高頻度に認めるが, 頑固な頭痛, 偏頭痛と判断されている場合も多い。経過中に精神症状が出現する場合は, ステロイド性精神病や二次的な心因反応との鑑別が難しい。
4)その他
 左右対象性の関節炎(40%)が手指などの小関節や, 膝, 手関節などの大関節でみられるが, その頻度は成人SLE(80%)ほどには多くはない。通常は一過性または移動性であり, Xp所見で骨びらんなどの破壊像がないのが特徴である。
 心病変の多くは心外膜炎で, 心嚢液貯留がみられる。稀に心内膜炎がみられるが, 三尖弁や僧帽弁に血栓性疣贅を形成する(Libman-Sacks心内膜炎)。
その他, 網膜炎, 肺出血, ループス腸炎, ループス膀胱炎など, 血管炎を基盤とした多彩な臨床像がみられる。
2.検査所見
1)一般検査
 末梢血では, 白血球(リンパ球)減少, 血小板減少, 溶血性貧血などが80%にみられる。赤沈は全例で中等度~高度亢進するが, CRPが陰性である点が特徴である。尿検査では, 尿蛋白, 血尿, 白血球円柱がみられる。生化学検査では, しばしば軽度の肝酵素の上昇がみられる。
2)免疫学的検査
 抗核抗体はほぼ全例で陽性である。また, 抗dsDNA抗体(96%)と抗Sm抗体(40%)はSLEに特異性が高く, 診断に有用である。抗リン脂質抗体が陽性(40%)であれば, 静脈や動脈に血栓症を発生するリスクがある(抗リン脂質抗体症候群)。低補体血症が発症早期から高頻度に認められ(80%), その程度は疾患活動性を反映する。
3)その他
 国際腎臓学会/国際腎病理学会のClass分類では, 腎炎のある小児SLEの約30%は腎機能予後が不良なClassⅣ型(びまん性腎炎)である。また尿所見に異常がなくても, 腎病理組織に異常所見を認める例が多い(silent lupus nephritis)。
脳の血流シンチやMRI検査では, 中枢神経症状を欠く例でも画像で異常を認める例が多い
診断
上記
治療
1.治療目標
 全身性血管炎病態を抑制し, 寛解状態を長期間維持することで, 臓器機能障害の発生や進行を抑止することが治療目標となる。また, ステロイドや免疫抑制薬による副作用を可能な限り低減することも, 長期にわたる治療の重要な目標である。
2.急性期の治療
 ステロイドが治療の基本である。病態の重篤性に応じて中~高用量のステロイド内服や点滴静注による大量ステロイドパルス療法が行われる。びまん性ループス腎炎や中枢神経ループスは予後不良な病態であり, このような病態を持つ症例では, ステロイドパルス療法に引き続き, 強力な免疫抑制療法の併用が開始される。その他, 抗凝固療法や血漿交換療法など, 病態に応じた治療が追加される。
3.寛解期の治療
 急性期治療で病態の寛解が得られれば, 寛解状態を維持しながら長期投与でも副作用が少ない投与量までステロイドを減量する。ステロイド減量中に再燃する場合は, ステロイド増量で対応するとともに, 併用する免疫抑制療法を強化することで, 少量ステロイドによる寛解病態を長期間維持し, 臓器障害の発生や進行を抑止する
予後
 小児SLEの累積10年生存率は98%であり, 生命予後は著しく改善した。しかし, 寛解と再燃を反復する病態に対しては, 今なお継続的な治療が必要であり, 長期寛解が得られない例では, 臓器障害の進行(腎不全, 中枢神経障害)や薬剤の副作用(大腿骨骨頭壊死, 骨粗鬆症)が問題となる。これらの永続的な問題のない小児SLEの累積10年生存率(event-free累積生存率)は66%に過ぎず, 臓器障害や機能障害の発生や進行に対し, まだ十分に抑止できていないのが現状である4)。

<指定難病49 全身性エリテマトーデス>
1.概要
 全身性エリテマトーデスはDNA-抗DNA抗体などの免疫複合体の組織沈着により起こる全身性炎症性病変を特徴とする自己免疫疾患である。症状は治療により軽快するものの, 寛解と増悪を繰り返して慢性の経過を取ることが多い。
 
2.原因
 一卵性双生児での全身性エリテマトーデスの一致率は25%程度であることから, 何らかの遺伝的素因を背景として, 感染, 性ホルモン, 紫外線, 薬物などの環境因子が加わって発症するものと推測されている。その結果, 自己抗体, 特に抗DNA抗体が過剰に産生され, 抗原であるDNAと結合して免疫複合体を形成される結果, 組織に沈着して補体系の活性化などを介して炎症が惹起されると考えられる。
 
3. 症状
(1)全身症状:全身倦怠感, 易疲労感, 発熱などが先行することが多い。
(2)皮膚・粘膜症状
 蝶形紅斑とディスコイド疹が特徴的である。日光暴露で増悪する。ディスコイド疹は顔面, 耳介, 頭部, 関節背面などによくみられ, 当初は紅斑であるが, やがて硬結, 角化, 瘢痕, 萎縮をきたす。この他凍瘡様皮疹, 頭髪の脱毛, 日光過敏も本症に特徴的である。
(3)筋・関節症状
 筋肉痛, 関節痛は急性期によくみられる。関節炎もみられるが, 骨破壊を伴うことはないのが特徴。
(4)腎症状:糸球体腎炎(ループス腎炎)は約半数の症例で出現し, 放置すると重篤となる。
(5)神経症状
 中枢神経症状を呈する場合は重症である(CNSループス)。うつ状態, 失見当識, 妄想などの精神症状と痙攣, 脳血管障害がよくみられる。
(6)心血管症状
 心外膜炎はよくみられ, タンポナーデとなることもある。心筋炎を起こすと, 頻脈, 不整脈が出現する。
(7)肺症状
 胸膜炎は急性期によくみられる。このほか, 間質性肺炎, 細胞出血, 肺高血圧症は予後不良の病態として注意が必要である。
(8)消化器症状:腹痛がみられる場合には, 腸間膜血管炎やループス腹膜炎に注意する。
(9)血液症状:溶血性貧血, 白血球減少や血小板減少も認められ, 末梢での破壊によると考えられている。
(10)その他:リンパ節腫脹は急性期によくみられる。
 
4.治療法
(1)非ステロイド系消炎鎮痛剤(NSAIDs)
 発熱, 関節炎などの軽減に用いられる。
(2)ステロイド剤
 全身性エリテマトーデスの免疫異常を是正するためには副腎皮質ステロイド剤の投与が必要不可欠である。一般には経口投与を行ない, 疾患の重症度により初回量を決定する。ステロイド抵抗性の症例では, ステロイド・パルス療法が用いられる。
 ステロイド抵抗性の症例やステロイド剤に対する重篤副作用が出現する症例においては, 免疫抑制剤の投与が考慮される。
(3)その他
 高血圧を伴う場合には, 腎機能障害の進行を防ぐためにも積極的な降圧療法が必要となる。腎機能が急速に悪化する場合には, 早期より血液透析への導入を考慮する。
 
5.予後
本症は寛解と増悪を繰り返し, 慢性の経過を取ることが多い。本症の早期診断, 早期治療が可能となった現在, 本症の予後は著しく改善し, 5年生存率は95%以上となった。
 予後を左右する病態としては, ループス腎炎, 中枢神経ループス, 抗リン脂質抗体症候群, 間質性肺炎, 肺胞出血, 肺高血圧症などが挙げられる。死因としては, 従来は腎不全であったが, 近年では日和見感染症による感染死が死因の第一位を占めている。

<指定難病診断基準>
① 顔面紅斑
② 円板状皮疹
③ 光線過敏症
④ 口腔内潰瘍 (無痛性で口腔あるいは鼻咽腔に出現)
⑤ 関節炎(2関節以上で非破壊性)
⑥ 漿膜炎 (胸膜炎あるいは心膜炎)
⑦ 腎病変 (0.5g/日以上の持続的蛋白尿か細胞性円柱の出現)
⑧ 神経学的病変 (痙攣発作あるいは精神障害)
⑨ 血液学的異常(溶血性貧血又は4,000/mm3以下の白血球減少又は1,500/mm3以下のリンパ球減少又は 10万/mm3以下の血小板減少)
⑩ 免疫学的異常(抗2本鎖 DNA 抗体陽性,抗 Sm 抗体陽性又は抗リン脂質抗体陽性(抗カルジオリピン抗体, ループスアンチコアグラント, 梅毒反応偽陽性)
⑪ 抗核抗体陽性 *抗核抗体

[診断のカテゴリー]
 上記項目のうち4項目以上を満たす場合, 全身性エリテマトーデスと診断する。

(機序) 母の Ro (可溶性の組織リボヌクレオタンパク) への IgE 抗体は, 発生中心の伝導系に障害を与える
(メモ)【リボヌクレオタンパク】ribonucleoprotein〈RNP〉《リボ核タンパク》
 RNAとタンパク質の複合体の名称. タンパク質はプロタミン, ヒストンなどの塩基性のものが多い. 細胞質に存在するリボソームは代表的なリボヌクレオタンパク質であるが, 核でも低分子RNA (snRNA) およびヘテロ接合体核RNA (hnRNA) はリボヌクレオタンパク質として存在している.
(頻度) 母の40%, SLE 母の胎児喪失率は30%
(責任遺伝子) *146790 Fc fragment of IgG, low affinity IIa, receptor for (FCG2A) <1q23.3>
.0001 Lupus nephritis, susceptibility to (152700) (Pseudomonas aeruginosa, susceptiblity to chronic infection by, in cystic fibrosis, included) (Malaria, severe, susceptibility to, included) [FCGR2A, ARG131HIS] (rs1801274) (gnomAD:rs1801274) (RCV000211160...) (Stein et al. 2000)
Susceptibility to Lupus Nephritis (Salmon et al. 1996; Moser et al. 1998)
Susceptibility to Chronic Infection by Pseudomonas Aeruginosa in Cystic Fibrosis (219700) (De Rose et al. 2005)
Susceptibility to Inflammatory Bowel Disease (266600) (Asano et al. 2009)
Susceptibility to Severe Malaria (611162) (Schuldt et al. 2010)

(責任遺伝子) *125505 Deoxyribonuclease I (DNASE1) <16p13.3>
.0001 Systemic lupus erythematosus, susceptibility to (152700) [DNASE1, LYS5TER] (Yasutomo et al. 2001)

(責任遺伝子) *600716 Protein-tyrosine phosphatase, nonreceptor-type 22 (PTPN22) <1p13.2>
.0001 Diabetes mellitus, insulin-dependent, susceptibility to (222100) [PTPN22, ARG620TRP] (180300 Rheumatoid arthritis, susceptibility to) (Systemic lupus erythematosus, susceptibility to 152700) (Hashimoto thyroiditis, susceptibility to included) (Addison disease, susceptibility to, included) (Bottini et al. 2004; Begovich et al. 2005; Criswell et al. 2005; Qu et al. 2005; Vang et al. 2005; Kawasaki et al. 2006; Kallberg et al. 2007; Huffmeier et al. 2006; The Wellcome Trust Case Control Consortium 2007; Rieck et al. 2007; Skinningsrud et al. 2008; Barrett et al. 2009; Mahdi et al. 2009; Arechiga et al. 2009; Zhang et al. 2011)
.0002 Diabetes mellitus, insulin-dependent, susceptibility to [PTPN22, -1123, G-C] (dbSNP:rs2488457) (Kawasaki et al. 2006)

(責任遺伝子) *604590 Fc fragment of IgG, low affinity IIb, receptor for (FCGR2B) <1q22>
.0001 Systemic lupus erythematosus [FCGR2B, -343G-C] (rs3219018) (RCV000005799) (Blank et al. 2005)
.0002 Systemic lupus erythematosus [FCGR2B, ILE232THR] (rs1050501) (gnomAD:rs1050501) (RCV000005800...) (Kyogoku et al. 2002; Floto et al. 2005; Kono et al. 2005; Clatworthy et al. 2007; Willcocks et al. 2010)

(ノート)
●(#) は,多くの遺伝子が SLE の原因に関与するという証拠のため

●全身性紅斑性狼瘡 (SLE)は慢性の弛張性反復性の炎症性でしばしば発熱性の全身結合織疾患で, 急性または潜行性発症をし, 原則として皮膚, 関節, 人および漿膜病変が特徴である
 原因不明であるが, 自己免疫系の調節メカニズム不全と考えられている

SLE の異質性
●SLEの遺伝的異質性はマッピングと分子遺伝学をみよ

●常染色体劣性型の SLE (SLEB16; 614420) は,3p14.3 の DNASE1L3 遺伝子 (602244) 変異が原因である

臨床症状
●Lappat and Cawein (1968) は, 薬剤誘発性, 特に procainamide-誘発性 SLE は薬剤遺伝性多型の発現である
 procainamide SLE 発端者の近い親戚で, 彼らは3例で血清の抗核抗体を発見した
  5人全員で, 免疫異常を示唆する有意な既往歴または検査所見を発見した
 3例は凝固異常をもっていた
 SLE 症例での補体欠損症の所見 (120900) と特異な HLA 型との連関は本疾患の家族集積に責任のある遺伝因子を指している
 他方, ウイルス病因の証拠は非遺伝的説明を示唆する
 SLE 様疾患が慢性肉芽腫症 (306400)の保因者で生じる (Schaller, 1972)

●Lessard ら(1997) は, CYP2D6 (124030) がN-hydroxyprocainamide 形成に含まれる主要な isozyme であることを証明した
 N-hydroxyprocainamide は procainamide で見られる薬剤誘発性ループス症候群に含まれる代謝産物である
 Lessard ら(1999) は遺伝的に決定されるまたは薬学的に仲介される CYP2D6 の活性低下が procainamide 治療中の薬剤誘発性ループスを予防できるかを証明するため今後の研究が必要であると述べた

●Reed ら(1972) は, 2世代で持続性結節を伴う炎症性血管炎を記載した
 最初の世代の女性3例が RA をもっていた
 彼らは日光での悪化と chloroquine での病変の抑制に気付いた
 彼らは lupus erythematosus profunda (Tuffanelli, 1971)に関係していると考えた
  これは家族発症をもちおそらく SLE に関係している
(メモ) 【深在性エリテマトーデス】lupus erythematosus profundus《深在性紅斑性狼瘡,ループス皮下脂肪組織炎;lupus panniculitis》
 皮下脂肪組織のエリテマトーデスで, 単独に出現するもの, 全身性エリテマトーデス・慢性円板状エリテマトーデスに伴うものがある. 30歳くらいの女性の顔・腰・上腕・大腿に5cm径くらいまでの皮下結節として出現し, 皮膚陥凹を残して治癒する. 皮下脂肪組織の肉芽腫と, ムチン変性ならびに血管壁の免疫グロブリンや補体の沈着がある.

●Brustein ら(1977) は, 円板状ループスの病変が2か月で生じた子供と SLE と思われる発疹が1週令で生じた第2子をもった円板状ループスの女性を記載した
●Sibley ら(1993) は, 男女同胞2例と彼らのめいが虚血性血管症を合併した SLE をもつ1家系を記載した
 1例の手足の写真は数本の指と全趾の壊疽を示していた
 めいには広範な骨壊死が生じた

●Elcioglu and Hall (1998) は, SLE の母から生まれた点状軟骨異形成の同胞2例を報告した
 1例は36週で死産し, 1例は母のSLEの悪化の後24週で流産した
●Austin-Ward ら(1998) は, SLE の母から生まれた新生児ループスおよび点状軟骨異形成の乳児1例を報告した
 乳児は経口抗凝固剤に暴露した (既往歴はなかった) 小児に類似した特徴ももっていた
●Elcioglu and Hall (1998) および Austin-Ward ら(1998)は, Toriello (1998) とともにこれら2論文の解説のなかで, 母 SLE と胎児点状軟骨異形成との間の連関の証拠があると示唆した
 しかし, この連関の機序は不明のままである
●Kelly ら(1999) は, 本疾患に典型的発疹をもつ新生児 SLE の男児乳児を報告した
 顔面中部低形成と多発性点状骨端をもっていた
 彼の母で SLE の診断へ導いたのは乳児の皮膚異常であった
 3年以上の経過観察で, 小児は著明な低身長, 顔面中部低形成, 指趾発達異常, 点状骨端のゆっくりした回復およびほぼ正常な認知発達を証明した

●Kamat ら(2003) は, SLE を生じた一卵性三胎児の証拠を初めて記載した
 SLE の診断は8, 9, 11歳でつけられた (出生の逆順で, 最後に生まれた子供が8歳で生じた)
 光線過敏性と皮膚病変が早期症状であった
 女児3例は異なる臨床兆候と症状を示したが, 全例に皮膚発疹, 易疲労性および生検で証明された糸球体腎炎があった
 検査所見は類似しており, 抗核抗体陽性, 抗DNA抗体陽性, 抗二重鎖DNA抗体陽性, 補体低値があった

SLE and Nephritis
Stein et al. (2002) analyzed 372 affected individuals from 160 multiplex SLE families, of which 25 contained at least 1 affected male relative. The presence of renal disease was significantly increased in female family members with an affected male relative compared to those with no affected male relative (p = 0.002); the trend remained after stratifying by race and was most pronounced in European Americans. Stein et al. (2002) concluded that the increased prevalence of renal disease previously reported in men with SLE is, in large part, a familial rather than sex-based difference, at least in multiplex SLE families.

Xing et al. (2005) added 392 individuals from 181 new multiplex SLE families to the sample previously studied by Stein et al. (2002) and replicated the finding that the prevalence of renal disease was increased in families with affected male relatives compared to families with no affected male relatives. Xing et al. (2005)concluded that multiplex SLE families with at least 1 affected male relative constitute a distinct subpopulation of multiplex SLE families.

その他の特徴
●DeHoratius ら(1975) は, SLE 患者の82%とその親戚の16%で抗-RNA 抗体を発見した (対照は5%)
 抗体をもった親戚は SLE と同居するものであった
 抗-RNA 抗体は SLE の血縁のない同居人にはなかった
 この所見は環境因子おそらくウイルスと遺伝的反応の両方が SLE の機序に含まれることを支持する
● Ro リボ核酸タンパクの情報は 601821 を参照

●Beaucher ら(1977) は, 2家系の同居犬で臨床および血清学的異常を発見した
 多数の臨床および血清学的 SLE と他の自己免疫疾患をもっていた
 自然 SLE は犬で生じるので, 伝達物質が含まれるかもしれない

●Horn ら(1978) は, 同胞8人中男女同胞2例で混合性結合織疾患 (MCTD) を記載した
 彼らは HLA-同一 (A11B12; A2B12)であった
 MCTD は SLE, 強皮症および多発性筋炎のオーバーラップする特徴をもつ
 血清は抗核抗体の関節免疫蛍光試験陽性で, 特徴的粗で斑点パターンをもつ
 診断はリボヌクレオタンパクへの抗体で確定される

●Batchelor ら(1980) は, ヒドララジン誘発性 SLE と HLA-DR4 との連関を発見した
 SLE のない緩徐 acetylators と非薬剤誘導性 SLE の症例は連関を示さなかった
 したがって, 自然 SLE は基本的に異なる疾患かもしれない
●Weinberg ら(1980) は, elliptocytosis and lipomatosis (151900) が独立した優性で分離する大家系で, 梅毒の生物学的偽陽性血清学的検査 (BFP STS)が高頻度であるのを発見した
 後者の形質も他の2形質と独立して優性にみえた
 BFP STS の女性2例が SLE を発症した

●Reidenberg ら(1980) は, SLE で slow acetylator 表現型が多いのを発見した
●Baer ら(1986) は, 反対に, acetylator 表現型と SLE の連関をみなかった
 文献のレビューから大多数の研究者は類似の結果をもつと結論した
●SLE に関係する多型の情報は C3b receptor (120620) をみよ

●Sakane ら(1989) は, SLE 患者6例の家系家族36人で, IL-2 活性アッセーと自然プラーク形成細胞アッセーを使ってT細胞とB細胞機能を調べた
 IL2 活性の障害が29人の親戚中15人で見つかったが, 発端者と同居する関連のない5人ではなかった
 B細胞アッセーは親戚29人中22人で異常であったが, 関連のない同居人5人中4人でも異常であった
 著者はSLE 患者の親戚にはIL2 活性障害の強い遺伝的成分があると結論した
  証拠はB細胞異常の遺伝的基礎を示唆したが, 環境の影響も役割をもつかもしれない
●Benke ら(1989) は, SLE 患者のサブグループからの PHA 刺激リンパ球で酸素代謝の増加を観察した
 著者は酸化活性の増加は in vivo で内因性DNAに化学的変化をつくり, SLE 患者の数例での自己免疫機序の最初の出来事何も知れないと示唆した

Using EMSA analysis, Solomou et al. (2001) showed that whereas stimulated T cells from normal individuals had increased binding of phosphorylated CREB (123810) to the -180 site of the IL2 promoter, nearly all stimulated T cells from SLE patients had increased binding primarily of phosphorylated CREM (123812) at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells.

Xu et al. (2004) demonstrated that activated T cells of lupus patients resisted anergy and apoptosis by markedly upregulating and sustaining cyclooxygenase-2 (COX2, or PTGS2; 600262) expression. Inhibition of COX2 caused apoptosis of the anergy-resistant lupus T cells by augmenting FAS (134637) signaling and markedly decreasing the survival molecule FLIP (603599), and this mechanism was found to involve anergy-resistant lupus T cells selectively. Xu et al. (2004) noted that the gene encoding COX2 is located in a lupus susceptibility region on chromosome 1. They also found that only some COX2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of PGE2. Xu et al. (2004) suggested that these findings could be useful in the design of lupus therapies.

Zhang et al. (2001) determined that SLE patients have increased serum levels of B-lymphocyte stimulator (BLYS, or TNFSF13B; 603969) compared with normal controls. Immunoprecipitation and Western blot analyses revealed expression of a 17-kD soluble form of BLYS in patients but not controls. Functional analysis demonstrated that most patient serum-derived BLYS exhibited increased costimulatory activity for B-cell proliferation in vitro. Patients with higher levels of BLYS also had significantly higher levels of anti-dsDNA in IgG, IgM, and IgA classes than did patients with low levels of BLYS. Although there was no correlation between increased BLYS levels and clinical SLE activity, there were slightly higher BLYS levels in patients with antinuclear antibodies (ANA) and significantly increased BLYS levels in patients with both ANA and a clinical impression of SLE, suggesting that elevated BLYS precedes the formal fulfillment of the criteria for SLE. Zhang et al. (2001) suggested that BLYS may play an antiapoptotic role in B-cell tolerance loss and that anti-BLYS may be a potential therapy for SLE and other autoimmune diseases.

Baechler et al. (2003) used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguished most SLE patients from healthy controls. Strikingly, approximately half of the patients studied showed dysregulated expression of genes in the interferon pathway. Furthermore, this interferon gene expression 'signature' served as a marker for more severe disease involving the kidneys, hematopoietic cells, and/or the central nervous system. These results provided insight into the genetic pathways underlying SLE, and identified a subgroup of patients who may benefit from therapies targeted at the interferon pathway.

Using ELISA, Balada et al. (2008) determined that the DNA deoxymethylcytosine content of purified CD4 (186940)-positive T cells was lower in patients with SLE than in controls. RT-PCR analysis detected no differences in DNMT1 (126375), DNMT3A (602769), or DNMT3B (602900) transcript levels between SLE patients and controls. However, simultaneous association of low complement counts with lymphopenia, high titers of anti-dsDNA, or a high SLE disease activity index resulted in an increase in at least 1 of the DNMTs. Balada et al. (2008) proposed that patients with active SLE and DNA hypomethylation have increased DNMT mRNA levels.

▼ Population Genetics
Kelly et al. (2002) stated that SLE primarily affects women of child-bearing age (F:M ratio, 9:1) and has a prevalence of approximately 1 case/2,500. Among African American populations, SLE is 3 times more prevalent than in European Americans, manifests at a younger age, and is more severe than in other American populations.

▼ Clinical Management
Glucocorticoids are widely used to treat patients with autoimmune diseases such as SLE. However, in the majority of SLE patients such treatment regimens cannot maintain disease control, and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reduction in disease activity. Guiducci et al. (2010) demonstrated that, in vitro and in vivo, stimulation of plasmacytoid dendritic cells (PDCs) through TLR7 (300365) and TLR9 (605474) can account for the reduced activity of glucocorticoids to inhibit the interferon pathway in SLE patients and in 2 lupus-prone mouse strains. The triggering of PDCs through TLR7 and TLR9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-kappa-B (see 164011) pathway essential for PDC survival. Glucocorticoids do not affect NF-kappa-B activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-alpha (147660) levels. Guiducci et al. (2010) concluded that their findings unveiled a new role for self nucleic acid recognition by TLRs and indicated that inhibitors of TLR7 and TLR9 signaling could prove to be effective corticosteroid-sparing drugs.

▼ Inheritance
Block et al. (1975) comprehensively reviewed evidence from twin studies. Higher concordance for clinical and serologic abnormality for monozygotic twins supported a significant genetic factor.

Lahita et al. (1983) observed father-to-son transmission and noted prepubertal onset of familial SLE in males.

Fielder et al. (1983) found an unexpectedly high frequency of null (silent) alleles at the C4A (120810), C4B (120820) and C2 (613927) loci in patients with SLE. HLA-DR3 showed a high frequency in these patients, and a strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B was found. On the basis of the data reported by Fielder et al. (1983), Green et al. (1986) concluded that association with null alleles at the C4 loci is primary and the DR3 association secondary to that. In addition to the association of SLE with MHC antigens DR2 and DR3 and with homozygous deficiency of early complement components, the fact that SLE occurs 3 to 4 times more frequently in blacks than in whites (Siegel et al., 1970; Fessel, 1974) points to genetic factors.

▼ Genotype/Phenotype Correlations
Sturfelt et al. (1990) found homozygous C4A deficiency in 13 of 80 patients (16%). Photosensitivity was a more impressive feature in these homozygotes than in other lupus patients. The T4/Leu-3 molecule (186940) is a T-cell differentiation antigen expressed on the surface of T helper/inducer cells. Monoclonal antibodies that can recognize this molecule include OKT4 and anti-Leu-3a, which bind to different determinants (epitopes) on the T4/Leu-3 molecule. This molecule has an important role in the recognition of class II MHC antigens by T cells. Polymorphism of the T4 epitope had, by the time of the report of Stohl et al. (1985), been identified only in blacks. Three phenotypes, corresponding to 3 genotypes, were identified: the most common, the T4 epitope-intact phenotype, is manifest when fluorescence intensity upon staining of T cells is as great with OKT4 as with anti-Leu-3a. The T4 epitope-deficient phenotype shows no staining with OKT4, and an intermediate phenotype, representing heterozygosity for deficiency, shows fluorescence intensity with OKT4 that is half that with anti-Leu-3a.

▼ Mapping
Genomewide Linkage Studies
Lee and Nath (2005) conducted a metaanalysis of 12 genome scans generated from 9 independent studies involving 605 SLE families with 1,355 affected individuals. They identified 2 loci, 6p22.3-6p21.1 and 16p12.3-16q12.2, that met genomewide significance (p less than 0.000417). Lee and Nath (2005) noted that 6p22.3-6p21.1 contains the HLA region.

Gaffney et al. (1998) reported the results of a genomewide microsatellite marker screen in 105 SLE sib-pair families. Eighty of the families were Caucasian; 5 were African American. By using multipoint nonparametric methods, the strongest evidence for linkage was found near the HLA locus; D6S257 gave a lod score of 3.90. D16S415 at 16q13 yielded a lod score of 3.64; D14S276 at 14q21-q23 yielded a lod score of 2.81; and D20S186 at 20p12 yielded a lod score of 2.62. Another 9 regions were identified with lod scores equal to or greater than 1.00. The data supported the hypothesis that multiple genes, including 1 in the HLA region, influence susceptibility to human SLE.

Gaffney et al. (2000) performed a second genomewide screen in a 'new' cohort of 82 SLE sib-pair families. Highest evidence of linkage was found in 4 intervals: 10p13, 7p22, 7q21, and 7q36; all 4 had a lod score greater than 2.0, and the locus on 7p22 had a lod score of 2.87. A combined analysis of cohorts 1 and 2 (187 sib-pair families total) showed that markers in 6p21-p11 (D6S426, lod score of 4.19) and 16q13 (D16S415, lod score of 3.85) met the criteria for significant linkage.

Using the ABI Prism linkage mapping set, which includes 350 polymorphic markers with an average spacing of 12 cM, Shai et al. (1999) screened the human genome in a sample of 188 lupus patients belonging to 80 lupus families, each with 2 or more affected relatives per family, to localize genetic intervals that may contain lupus susceptibility loci. Nonparametric multipoint linkage analysis suggested evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, support for a gene in the 1q44 region, as well as for a gene in the 1p36 region, was found clearly only in Mexican American families with SLE, but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.

Lindqvist et al. (2000) performed genome scans in families with multiple SLE patients from Iceland and from Sweden. A number of regions gave lod scores greater than 2: among Icelandic families, 4p15-p13, Z = 3.20; 9p22, Z = 2.27; and 19q13, Z = 2.06, which are homologous to the murine regions containing the lmb2, sle2, and sle3 loci, respectively. The fourth region among Icelandic families is located on 19p13 (D19S247, Z = 2.58) and a fifth on 2q37 (D2S125, Z = 2.06). Only 2 regions showed lod scores above 2.0 in the Swedish families: 2q11 (D2S436, Z = 2.13) and 2q37 (D2S125, Z = 2.18). The combination of both family sets gave a highly significant lod score at D2S125, with a Z of 4.24 in favor of linkage for 2q37 (see 605218).

Gray-McGuire et al. (2000) presented the result of a genome scan of 126 pedigrees with 2 or more cases of SLE, including 469 sib pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sib pairs and a conditional logistic regression technique for affected relative pairs, they identified linkage to chromosome 4p16-p15.2 (P = 0.0003, lod = 3.84) and presented evidence of an epistatic interaction between 4p16-p15.2 and chromosome 5p15 in European American families. Using data from an independent pedigree collection, they confirmed the linkage to 4p16-p15.2 in European American families. The most significant linkage that they found in the African American subset was to the previously identified region on 1q (601744).

Johanneson et al. (2002) genotyped a set of 87 multicase families with SLE from various European countries and recently admixed populations of Mexico, Colombia, and the United States for 62 microsatellite markers on chromosome 1. By parametric 2-point linkage analysis, 6 regions previously described as being related to SLE (1p36, 1p21, 1q23, 1q25, 1q31, and 1q43) were identified that had lod scores greater than or equal to 1.50. CD45 (151460) was considered a strong candidate gene because of its position in 1q31-q32 and because of its involvement in the regulation of the antigen-induced signaling of naive B and T cells. Johanneson et al. (2002) found no association between the 77C-G (151460.0001) mutation in the CD45 gene and SLE in the families they studied. The locus at 1q31 showed a significant 3-point lod score of 3.79 and was contributed by families from all populations, with several markers and under the same parametric model. They concluded that a locus at 1q31 contains a major susceptibility gene, important to SLE in 'general populations.'

Scofield et al. (2003) selected 38 pedigrees that had an SLE patient with thrombocytopenia from a collection of 184 pedigrees with multiple cases of SLE. They established linkage at chromosome 1q22-q23 (maximum lod = 3.71) in all 38 pedigrees and at 11p13 (maximum lod = 5.72) in the 13 African American pedigrees. Nephritis, serositis, neuropsychiatric involvement, autoimmune hemolytic anemia, anti-double-stranded DNA, and antiphospholipid antibody were associated with thrombocytopenia. The results showed that SLE was more severe in the families with a thrombocytopenic SLE patient, whether or not thrombocytopenia in an individual patient was considered.

Susceptibility Loci for SLE Mapped by Linkage Studies
See SLEB1 (601744) for discussion of an SLE susceptibility locus on chromosome 1q41. Variations in the TLR5 gene (603031) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB2 (605218) for discussion of an SLE susceptibility locus on chromosome 2q37. Variations in the PDCD1 gene (605218) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB3 (605480) for discussion of an SLE susceptibility locus on chromosome 4p.

See SLEB4 (608437) for discussion of an SLE susceptibility locus on chromosome 12q24.

See SLEB5 (609903) for discussion of an SLE susceptibility locus on chromosome 13q32.

See SLEB6 (609939) for discussion of an SLE susceptibility locus on chromosome 16q12-q13.

See SLEB7 (610065) for discussion of an SLE susceptibility locus on chromosome 20p12.

See SLEB8 (610066) for discussion of an SLE susceptibility locus on chromosome 20q13.1.

See SLEB9 (610927) for discussion of an SLE susceptibility locus on chromosome 1q32.

See SLEB10 (612251) for discussion of an SLE susceptibility locus on chromosome 7q32. Variations in the IRF5 gene (607218) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB11 (612253) for discussion of an SLE susceptibility locus on chromosome 2q32.2-q32.3. Variations in the STAT4 gene (600558) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB12 (612254) for discussion of an SLE susceptibility locus on chromosome 8p23.1.

See SLEB13 (612378) for discussion of an SLE susceptibility locus on chromosome 6p23. Variations in the TNFAIP3 gene (191163) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB14 (613145) for discussion of an SLE susceptibility locus on chromosome 1q21-q23. Variations in the CRP gene (123260) have been associated with SLE at this locus; see MOLECULAR GENETICS.

See SLEB15 (300809) for a discussion of an SLE susceptibility locus on chromosome Xq28.

Susceptibility Loci for SLE with Nephritis
Renal disease occurs in 40 to 75% of SLE patients and contributes significantly to morbidity and mortality (Garcia et al., 1996). Quintero-Del-Rio et al. (2002) used 2 pedigree stratification strategies to explore the impact of the American College of Rheumatology's renal criterion for SLE classification upon genetic linkage with SLE. They identified susceptibility loci for SLE associated with nephritis on chromosomes 10q22.3 (SLEN1; 607965), 2q34-q35 (SLEN2; 607966), and 11p15.6 (SLEN3; 607967).

Susceptibility Locus for SLE with Hemolytic Anemia
A locus for susceptibility to SLE with hemolytic anemia as an early or prominent clinical manifestation shows linkage to 11q14 (SLEH1; 607279).

Susceptibility Locus for SLE with Vitiligo
A locus for susceptibility to SLE associated with vitiligo has been mapped to 17p13 (SLEV1; 606579).

Association with the HLA-DRB1 Locus
Using a dense map of polymorphic microsatellites across the HLA region in a large collection of families with SLE, Graham et al. (2002) identified 3 distinct haplotypes that encompassed the class II region and exhibited transmission distortion. By visualizing ancestral recombinants, they narrowed the disease-associated haplotypes containing DRB1*1501 and DRB1*0801 to a region of approximately 500 kb. They concluded that HLA class II haplotypes containing DRB1 and DQB1 alleles are strong risk factors for human SLE.

To identify risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This new cohort replicated the association with HLA-DRB1 at rs3135394 (odds ratio = 1.98, 95% confidence interval = 1.84-2.14; combined P = 2.0 x 10(-60)).

Association with the TNIP1 Gene on Chromosome 5q32
In a study of 1,963 patients from the United States and Sweden with SLE compared with 4,329 controls, Gateva et al. (2009) identified association with the TNIP1 gene (607714) at chromosome 5q32 (rs7708392, combined P value = 3.8 x 10(-13); odds ratio = 1.27, 95% confidence interval = 1.10-1.35).

Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with a SNP in the TNIP1 gene, rs10036748 (combined P = 1.67 x 10(-9); odds ratio = 0.81, 95% confidence interval = 0.75-0.87).

▼ Molecular Genetics
Association with the PTPN22 Gene on Chromosome 1p13
In a study of 525 unrelated North American white individuals with SLE, Kyogoku et al. (2004) found an association with the R620W polymorphism in the PTPN22 gene (600716.0001), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increased risk of SLE (odds ratio = 1.37), and 2 copies of the allele more than doubled this risk (odds ratio = 4.37).

Orru et al. (2009) reported a 788G-A variant, resulting in an arg263-to-gln (R263Q; rs33996649) substitution within the catalytic domain of the PTPN22 gene, that leads to reduced phosphatase activity. They genotyped 881 SLE patients and 1,133 healthy controls from Spain and observed a significant protective effect (p = 0.006; OR, 0.58). Three replication cohorts of Italian, Argentinian, and Caucasian North American populations failed to reach significance; however, the combined analysis of 2,093 SLE patients and 2,348 controls confirmed the protective effect (p = 0.0017; OR, 0.63).

To confirm additional risk loci for SLE susceptibility, Gateva et al. (2009) selected SNPs from 2,466 regions that showed nominal evidence association to SLE (P less than 0.05) in a genomewide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. Gateva et al. (2009) showed an association with PTPN22 at rs2476601 (combined P value = 3.4 x 10(-12), odds ratio = 1.35, 95% confidence interval = 1.24-1.47).

Association with the CRP Gene on Chromosome 1q21-q23
Relative deficiency of pentraxin proteins is implicated in the pathogenesis of SLE. The C-reactive protein (CRP; 123260) response is defective in patients with acute flares of disease, and mice with targeted deletions of the APCS (104770) gene develop a lupus-like illness. In humans, the CRP and APCS genes are both within the 1q23-q24 interval that has been linked to SLE. Among 586 simplex SLE families, Russell et al. (2004) found that basal levels of CRP were influenced independently by 2 CRP polymorphisms, which they designated CRP2 (rs1800947) and CRP4 (rs1205), and the latter was associated with SLE and antinuclear autoantibody production. Russell et al. (2004) hypothesized that defective disposal of potentially immunogenic material may be a contributory factor in lupus pathogenesis.

Association with the FCGR2B Gene on Chromosome 1q22
In 193 Japanese patients with SLE and 303 healthy controls, Kyogoku et al. (2002) found that homozygosity for an ile232-to-thr polymorphism in the FCGR2B gene (I232T; 604590.0002) was significantly increased in SLE patients compared with controls.

In membrane separation studies using a human monocytic cell line, Floto et al. (2005) demonstrated that although wildtype FCGR2B readily partitioned into the raft-enriched gradient fractions, FCGR2B-232T was excluded from them. Floto et al. (2005) concluded that FCGR2B-232T is unable to inhibit activating receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE.

Su et al. (2004) identified 10 SNPs in the first FCGR2B promoter in 66 SLE patients and 66 controls. They determined that the proximal promoter contains 2 functionally distinct haplotypes. Luciferase promoter analysis showed that the less frequent haplotype, which had a frequency of 9%, was associated with increased gene expression. A case-control study of 243 SLE patients and 366 matched controls demonstrated that the less frequent haplotype was significantly associated with the SLE phenotype and was not in linkage disequilibrium with FCGR2A and FCGR3A (146740) polymorphisms. Su et al. (2004) concluded that an expression variant of FCGR2B is a risk factor for SLE.

In 190 European American patients with SLE and 130 European American controls, Blank et al. (2005) found a significant association between homozygosity for a -343C polymorphism in the promoter region of the FCGR2B gene (604590.0001) and SLE. The surface expression of FCGR2B receptors was significantly reduced in activated B cells from -343C/C SLE patients. Blank et al. (2005) suggested that deregulated expression of the mutant FCGR2B gene may play a role in the pathogenesis of human SLE.

By comparing genotypes of patients with SLE from Hong Kong and the UK with those of ethnically matched controls, followed by metaanalysis using with other studies on southeast Asian and Caucasian SLE patients, Willcocks et al. (2010) found that homozygosity for T232 of the I232T FCGR2B polymorphism was strongly associated with SLE in both ethnic groups. When studies in Caucasians and southeast Asians were combined, T232 homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0 x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP is more common in southeast Asians and Africans, populations where malaria (see 611162) is endemic, than in Caucasians. Homozygosity for T232 was significantly associated with protection from severe malaria in Kenyan children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was found with susceptibility to bacterial infection. Willcocks et al. (2010) proposed that malaria may have driven retention of a polymorphism predisposing to a polygenic autoimmune disease and thus may begin to explain the ethnic differences seen in the frequency of SLE.

Association with the FCGR3B Gene on Chromosome 1q23
Aitman et al. (2006) showed that copy number variation (CNV) of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the rat-specific Fcgr3 paralog 'Fcgr3-related sequence' (Fcgr3rs) as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B (610665), an ortholog of rat Fcgr3, was associated with glomerulonephritis in SLE.

Following up on the study of Aitman et al. (2006) in a larger sample, Fanciulli et al. (2007) confirmed and strengthened their previous finding of an association between low FCGR3B copy number and susceptibility to glomerulonephritis in SLE patients. Low copy number was also associated with risk of systemic SLE with no known renal involvement as well as with microscopic polyangiitis and Wegener granulomatosis (608710), but not with organ-specific Graves disease (275000) or Addison disease (240200), in British and French cohorts. Fanciulli et al. (2007) concluded that low FCGR3B copy number or complete FCGR3B deficiency has a key role in the development of specific autoimmunity.

Willcocks et al. (2008) confirmed that low copy number of FCGR3B was associated with SLE in a Caucasian U.K. population, but they were unable to find an association in a Chinese population. Investigations of the functional effects of FCGR3B CNV revealed that FCGR3B CNV correlated with cell surface expression, soluble FCGR3B production, and neutrophil adherence to and uptake of immune complexes both in a patient family and in the general population. Willcocks et al. (2008) found that individuals from 3 U.K. cohorts with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) were more likely to have high FCGR3B CNV. They proposed that FCGR3B CNV is involved in immune complex clearance, possibly explaining the association of low CNV with SLE and high CNV with AASV.

Niederer et al. (2010) noted linkage disequilibrium (LD) between multiallelic FCGR3B CNV and SLE-associated SNPs in the FCGR locus. Despite LD between FCGR3B CNV and a variant in FCGR2B (I232T; 604590.0002) that abolishes inhibitory function, both reduced CN of FCGR3B and homozygosity of the FCGR2B-232T allele were individually strongly associated with SLE risk. Thus copy number of FCGR3B, which controls immune complex responses and uptake by neutrophils, and variations in FCGR2B, which controls factors such as antibody production and macrophage activation, are important in SLE pathogenesis.

Mueller et al. (2013) found that the increased risk of SLE associated with reduced copy number of FCGR3B can be explained by the presence of a chimeric gene, FCGR2B-prime, that occurs as a consequence of FCGR3B deletion on FCGR3B zero-copy haplotypes. The FCGR2B-prime gene consists of upstream elements and a 5-prime coding region that derive from FCGR2C, and a 3-prime coding region that derives from FCGR2B (604590). The coding sequence of FCGR2B-prime is identical to that of FCGR2B, but FCGR2B-prime would be expected to be under the control of 5-prime flanking sequences derived from FCGR2C. Mueller et al. (2013) found by flow cytometry, immunoblotting, and cDNA sequencing that presence of the chimeric FCGR2B-prime gene results in the ectopic presence of Fc-gamma-RIIb on natural killer cells, providing an explanation for SLE risk associated with reduced FCGR3B copy number. The 5 FCGR2/FCGR3 genes are arranged across 2 highly paralogous genomic segments on chromosome 1q23. To pursue the underlying mechanism of SLE disease association with FCGR3B copy number variation, Mueller et al. (2013) aligned the reference sequence (GRCh37) of the proximal block of the FCGR locus (chr1:161,480,906-161,564,008) to that of the distal block (chr1:161,562,570-161,645,839). Identification of informative paralogous sequence variants (PSVs) enabled Mueller et al. (2013) to narrow the potential breakpoint region to a 24.5-kb region of paralogy between then 2 ancestral duplicated blocks. The complete absence of nonpolymorphic PSVs in the 24.5-kb region prevented more precise localization of the breakpoints in FCGR3B-deleted or FCGR3B-duplicated haplotypes.

Association with the TNFSF6 Gene on Chromosome 1q23
The apoptosis genes FAS (TNFRSF6; 134637) and FASL (TNFSF6; 134638) are candidate contributory genes in human SLE, as mutations in these genes result in autoimmunity in several murine models of this disease. In humans, FAS mutations result in a familial autoimmune lymphoproliferative syndrome (e.g., 134637.0001). Wu et al. (1996) studied DNA from 75 patients with SLE using SSCP analysis for potential mutations of the extracellular domain of FASL. In 1 SLE patient who exhibited lymphadenopathy, they found an 84-bp deletion within exon 4 of the FASL gene, resulting in a predicted 28-amino acid in-frame deletion (see 134638.0001).

Association with the TNFSF4 Gene on Chromosome 1q25
By use of both a family-based study and a case-control study of SLE in U.K. and Minnesota populations to screen the TNFRSF4 (600315) and TNFSF4 (603594) genes, Graham et al. (2008) found that an upstream region of TNFSF4 contains a single risk haplotype (GCTAATCATTTGA) for SLE that correlates with increased cell surface TNFSF4 expression and TNFSF4 transcript. The authors suggested that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T-cell/antigen-presenting cell (APC) interaction or by influencing the functional consequences of T-cell activation via TNFRSF4.

Han et al. (2009) performed a genomewide association study of SLE in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina-Human610-Quad BeadChips and replicating 78 SNPs in 2 additional cohorts (3,152 cases and 7,050 controls). Han et al. (2009) found association with the TNFSF4 gene at 2 SNPs, rs1234315 (combined P value = 2.34 x 10(-26), odds ratio = 1.37, 95% confidence interval 1.29-1.45) and rs2205960 (combined P value = 2.53 x 10(-32), odds ratio = 1.46, 95% confidence interval 1.37-1.56).

Association with the CR2 Gene on Chromosome 1q32
Wu et al. (2007) analyzed the CR2 gene, which lies in the SLEB9 (610927) locus region, in 1,416 individuals from 258 Caucasian and 142 Chinese SLE simplex families and demonstrated that a common 3-SNP haplotype (120650.0001) was associated with SLE susceptibility (p = 0.00001) with a 1.54-fold increased risk for development of disease. Wu et al. (2007) concluded that the CR2 gene is likely a susceptibility gene for SLE.

Association with the TLR5 Gene on Chromosome 1q41-q42
A polymorphism in the TLR5 gene (R392X; 603031.0001), which maps to the SLEB1 (601744) locus, is associated with resistance to SLE development.

Association with the STAT4 Gene on Chromosome 2q32
In 1,039 patients with SLE and 1,248 controls, Remmers et al. (2007) identified an association between SLE (SLEB11; 612253) and the minor T allele of rs7574865 in intron 3 of the STAT4 gene (600558.0001). The risk allele was present in 31% of chromosomes of patients with SLE compared with 22% of those of controls (p = 1.87 x 10(-9)). Homozygosity of the risk allele (TT) compared to absence of the allele was associated with a more than doubled risk for lupus. The risk allele was also associated with susceptibility to rheumatoid arthritis (RA; 180300).

Association with the CTLA4 Gene on Chromosome 2q33
In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between an 49A-G polymorphism in the CTLA4 gene (123890.0001) and SLE. The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE.

In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians.

Association with the PDCD1 Gene on Chromosome 2q37
Prokunina et al. (2002) analyzed 2,510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in the PDCD1 gene, which maps within the SLEB2 locus (605218). They showed that one intronic SNP (600244.0001) was associated with development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1; 151385) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.

Association with the TREX1 Gene on Chromosome 3p21
Lee-Kirsch et al. (2007) analyzed the 3-prime repair exonuclease gene TREX1 (606609) in 417 patients with SLE and 1,712 controls and identified heterozygosity for a 3-prime UTR variant and 11 nonsynonymous changes in 12 patients (see, e.g., 606609.0001). They identified only 2 nonsynonymous changes in 2 controls (p = 1.7 X 10(-7), relative risk = 25.3). In vitro studies of 2 frameshift mutations revealed that both caused altered subcellular distribution. The authors concluded that TREX1 is implicated in the pathogenesis of SLE.

Association with the BANK1 Gene on Chromosome 4q22-q24
Kozyrev et al. (2008) identified an association between SLE and a nonsynonymous G-to-A transition in the BANK1 gene that results in a substitution of his for arg at codon 61 (610292.0001), with the G allele conferring risk.

Association with the NKX2-5 Gene on Chromosome 5q34
Oishi et al. (2008) genotyped 3 SNPs in the NKX2-5 gene (600584) in 178 Japanese SLE patients and 1,425 controls and found association with rs3095870 in the 5-prime flanking region of NKX2-5 (p = 0.0037; odds ratio, 1.74). Individuals having the risk genotype for both NKX2-5 and 3748079 of the ITPR3 gene (147267) had a higher risk for SLE (odds ratio, 5.77).

Association with the ITPR3 Gene on Chromosome 6p21
Oishi et al. (2008) performed a case-control association study using more than 50,000 genomewide gene-based SNPs in a total of 543 Japanese SLE patients and 2,596 controls and identified significant association with a -1009C-T transition (rs3748079) located in a promoter region of the ITPR3 gene (p = 1.78 x 10(-8); odds ratio, 1.88). Studies in HEK293T cells showed that binding of NKX2-5 is specific to the nonsusceptibility -1009T allele, and individuals with the risk genotype of both ITPR3 and NKX2-5 (rs3095870) had a higher risk for SLE (odds ratio, 5.77). Oishi et al. (2008) concluded that genetic and functional interactions of ITPR3 and NKX2-5 play a crucial role in the pathogenesis of SLE.

Association with the TNFA Gene on Chromosome 6p21.3
In a metaanalysis of 19 studies, Lee et al. (2006) found an association between SLE and a -308A/G promoter polymorphism in the TNFA gene (191160.0004). The findings were significant in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations.

Association with the C4A and C4B Genes on Chromosome 6p21.3
In a metaanalysis of 19 studies, Lee et al. (2006) found an association between SLE and a -308A/G promoter polymorphism in the TNFA gene (191160.0004). The findings were significant in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations.

Association with the C4A and C4B Genes on Chromosome 6p21.3
Yang et al. (2007) investigated interindividual gene copy number variation (CNV) of complement component C4 in relation to susceptibility to SLE. They found that long C4 genes were strongly correlated with C4A (120810); short C4 genes were correlated with C4B (120820). In comparison with healthy subjects, patients with SLE clearly had the gene copy number (GCN) of total C4 and C4A shifted to the lower side. The risk of SLE disease susceptibility increased significantly among subjects with only 2 copies of total C4 (patients 9.3%; unrelated controls 1.5%) but decreased in those with 5 or more copies of C4 (patients 5.79%; controls 12%). Zero copies and 1 copy of C4A were risk factors for SLE, whereas 3 or more copies of C4A appeared to be protective. Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of TNFA (191160.0004) was more likely to be transmitted to patients with SLE.

Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.

Association with the TNXB Gene on Chromosome 6p21.3
In a genomewide case-control association study of 178 Japanese SLE patients and 899 controls, Kamatani et al. (2008) found significant association between SLE and a SNP (rs3130342) in the 5-prime flanking region of the TNXB gene (600985) on chromosome 6p21.3 (p = 9.3 x 10(-7); odds ratio, 3.11). The association was replicated independently with 203 cases and 294 controls (p = 0.04; odds ratio, 1.52). Analysis in their Japanese SLE patients showed that the association with rs3130342 was independent of C4 copy number, suggesting that the association previously reported between SLE and CNV of the C4A gene (see Yang et al., 2007) likely reflected linkage disequilibrium between C4A CNV and rs3130342. Stratified analysis also demonstrated that the association between rs3130342 and SLE was independent of the HLA-DRB1*1501 allele association with SLE. Kamatani et al. (2008) concluded that TNXB is a candidate gene for SLE susceptibility in the Japanese population.

Association with the TNFAIP3 Gene on Chromosome 6q23
In separate genomewide association studies, Graham et al. (2008) and Musone et al. (2008) found association between single-nucleotide polymorphisms (SNPs) in the TNFAIP3 region (191163) and risk of SLE. Graham et al. (2008) found association with SLE of a SNP that is also associated with rheumatoid arthritis (RA; 180300).

Association with the IRF5 Gene on Chromosome 7q32
Sigurdsson et al. (2005) and Graham et al. (2006) showed that a common IRF5 (607218) haplotype, which drives elevated expression of multiple unique forms of IRF5, is an important risk factor for SLE (SLEB10; 612251).

Association with the DNASE1 Gene on Chromosome 16p13.3
In 2 unrelated females with SLE and no family history of the disorder, Yasutomo et al. (2001) identified heterozygosity for a mutation in the DNASE1 gene (125505.0001). The patients, aged 13 and 17 years, were diagnosed as having SLE based on clinical features, high serum titers of antibodies against double-stranded DNA, and Sjogren syndrome. Both patients had substantially lower levels of DNASE1 activity in the sera than in other SLE patients without a DNASE1 mutation. However, the DNASE1 activity of SLE patients without DNASE1 mutations is lower than that of healthy controls. The patient's B cells had 30 to 50% of the DNASE1 activity of cells from controls, showing that heterozygous mutation of DNASE1 reduces the total activity of this enzyme.

In 350 Korean patients with SLE and 330 Korean controls, Shin et al. (2004) identified a nonsynonymous SNP in exon 8 of the DNASE1 gene, 2373A-G (Q244R; 125505.0002), that was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the arg/arg minor allele was much higher in patients who had the anti-RNP antibody (31%) than in patients who did not have this antibody (14%) (P = 0.0006).

Association with the ITGAM Gene on Chromosome 16p11.2
See SLEB6, 609939.

Nath et al. (2008) identified and replicated an association between ITGAM (120980) at 16p11.2 and risk of SLE in 3,818 individuals of European descent. The strongest association was at a nonsynonymous SNP, rs1143679 (120980.0001). Nath et al. (2008) further replicated this association in 2 independent samples of individuals of African descent. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) likewise identified an association between SNPs in ITGAM in 720 women of European ancestry with SLE and in 2 additional independent sample sets. Several previously identified associations such as the strong association between SLE and the HLA region on 6p21 and the previously confirmed non-HLA locus IRF5 (607218) on 7q32 were found. The International Consortium for Systemic Lupus Erythematosus Genetics et al. (2008) also found association with replication for KIAA1542 (611780) at 11p15.5, PXK (611450) in 3p14.3, and a SNP at 1q25.1.

Hom et al. (2008) identified SNPs near the ITGAM and ITGAX (151510) genes that were associated with SLE; they believed variants of ITGAM to be driving the association.

Association with the IL6 Gene on chromosome 7p21
Linker-Israeli et al. (1999) used PCR and RFLP analysis to genotype the AT-rich minisatellite in the 3-prime flanking region and the 5-prime promoter-enhancer of IL6 (147620) in SLE patients and controls. In both African-Americans and Caucasians, short allele sizes (less than 792 bp) at the 3-prime minisatellite were found exclusively in SLE patients, whereas the 828-bp allele was overrepresented in controls. No association was found between SLE and alleles in the 5-prime region of IL6. Patients homo- or heterozygous for the SLE-associated 3-prime minisatellite alleles secreted higher levels of IL6, had higher percentages of IL6-positive monocytes, and showed significantly enhanced IL6 mRNA stability. Linker-Israeli et al. (1999) concluded that the AT-rich minisatellite in the 3-prime region flanking of IL6 is associated with SLE, possibly by increasing accessibility for transcription factors.

Association with the IL18 Gene on Chromosome 11q22
Sanchez et al. (2009) selected 9 SNPs spanning the IL18 gene (600953) and genotyped an independent set of 752 Spanish systemic lupus erythematosus patients and 595 Spanish controls. A -1297T-C SNP (rs360719) survived correction for multiple tests and was genotyped in 2 case-control replication cohorts from Italy and Argentina. Combined analysis for the risk C allele remained significant (pooled odds ratio = 1.37, 95% CI 1.21-1.54, corrected p = 1.16 x 10(-6)). There was a significant increase in the relative expression of IL18 mRNA in individuals carrying the risk -1297C allele; in addition, -1297C allele created a binding site for the transcriptional factor OCT1 (POU2F1; 164175). Sanchez et al. (2009) suggested that the rs360719 variant may play a role in susceptibility to SLE and in IL18 expression.

Association with the CSK Gene on Chromosome 15q23-q25
The c-Src tyrosine kinase CSK (124095) physically interacts with the intracellular phosphatase LYP (PTPN22; 600716) and can modify the activation state of downstream Src kinases, such as LYN (165120), in lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of CSK with SLE and refined its location to the intronic polymorphism rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of LYN. In carriers of the risk allele, there is increased B-cell receptor-mediated activation of mature B cells, as well as higher concentrations of plasma IgM, relative to individuals in the nonrisk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results suggested that the LYP-CSK complex increases susceptibility to lupus at multiple maturation and activation points in B cells.

Association with the EGR2 Gene on Chromosome 10q21
Based on phenotypic changes in knockout mice, Myouzen et al. (2010) evaluated if polymorphisms in the EGR2 gene (129010) on chromosome 10q21 influence SLE susceptibility in humans. A significant positive correlation with expression was identified in a SNP located at the 5-prime flanking region of EGR2. In a case-control association study using 3 sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region, a peak of association with SLE susceptibility was observed for rs10761670. This SNP was also associated with susceptibility to rheumatoid arthritis (RA; 180300), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670, 2 SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. The authors proposed that EGR2 may be a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.

Association with the NCF1 Gene on Chromosome 7q11
Zhao et al. (2017) reported a missense variant (g.74779296G-A; rs201802880, arg90 to his) in exon 4 of NCF1, encoding the p47-phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by SNP microarray analysis in the GTF2IRD1 (604318)-GTF2I (601679) region on chromosome 7q11.23 with a complex genomic structure. Zhao et al. (2017) showed that the arg90-to-his (R90H) substitution, which was reported by Olsson et al. (2012) to cause reduced reactive oxygen species (ROS) production, was associated with SLE (odds ratio (OR) = 3.47 in Asians (p-meta = 3.1 x 10(-104)), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjogren syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, Zhao et al. (2017) found that decreased and increased copy numbers of NCF1 were associated with predisposition to and protection against SLE, respectively. These data highlighted the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

Association with the MEF2D Gene on Chromosome 1q22
Using targeted sequencing of coding and conserved regulatory regions within and around 215 SLE candidate genes selected on the basis of their known role in autoimmunity and/or association with canine immune-mediated diseases, Farias et al. (2019) identified a rare regulatory variant in intron 4 of the MEF2D (600663) gene, rs200395694G-T, that was associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls; p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the variant and a triad of disease manifestations, including Raynaud phenomenon, anti-U1-RNP, and anti-Smith antibodies (p = 0.00037), among the patients. Functional studies revealed that the region has properties of an active cell-specific enhancer and that the risk allele affects tissue-specific splicing.

▼ Pathogenesis
The role of estrogen in determining female preponderance of lupus was reviewed by Talal (1979). Patients with the XXY Klinefelter syndrome are predisposed to lupus. Miller and Schwartz (1979) proposed 'that the development of systemic lupus erythematosus requires the participation of at least two functionally distinct classes of genes.'
Stohl et al. (1985) identified 3 unrelated Jamaican black patients with SLE by American Rheumatism Association criteria (Tan et al., 1982) and with homozygous T4 epitope deficiency. Lymphadenopathy was an impressive feature and was present also in an asymptomatic and otherwise apparently healthy T4-deficient brother of one of the SLE patients. In 1 family, 2 heterozygotes had Hb Constant Spring and 1 had idiopathic thrombocytopenic purpura. The anti-DNA antibodies of unrelated SLE patients share cross-reactive idiotypes. Thus, a restricted number of germline genes may encode the autoantibodies involved in the pathogenesis of SLE.

Solomon et al. (1983) described a monoclonal antibody, 3I, that recognizes a cross-reactive idiotype on anti-DNA antibodies. Halpern et al. (1985) used this monoclonal antibody to study the sera of 27 members of 3 unrelated kindreds with SLE. Some healthy family members were found to have high-titered reactivity with the antiidiotype. The antigenic specificity of 3I-reactive antibodies in the serum of healthy persons is unknown. Possibly 3I-reactive antibodies are made in response to some unknown antigen and these antibodies subsequently mutate and acquire reactivity with DNA. Diamond and Scharff (1984) showed that a monoclonal antiphosphorylcholine antibody that has undergone a glutamic to alanine substitution in a heavy chain hypervariable region loses affinity for phosphorylcholine and acquires reactivity with DNA and other phosphorylated macromolecules.

Schur (1995) reviewed the genetics of SLE, with particular reference to the major histocompatibility complex. He showed that different but related genes may be associated with lupus and autoantibodies in different countries. He suggested that examination of homogeneous (clinical, immunologic, ethnic, etc.) populations offers the best possibility for unraveling the maze of multiple genes involved in the disorder.

Kotzin (1996) reviewed the molecular mechanisms in the pathogenesis of SLE. Vyse and Todd (1996) gave a general review of genetic analysis of autoimmune diseases, including this one.

Sanghera et al. (1997) noted that beta-2-glycoprotein I (B2GPI, APOH; 138700) is a required cofactor for anionic phospholipid binding by the antiphospholipid autoantibodies found in sera of many patients with SLE and primary antiphospholipid syndrome (107320). These studies suggested that the apoH-phospholipid complex forms the antigen to which the autoantibodies are directed.

Yasutomo et al. (2001) identified an early termination mutation in DNASE1 in 2 teenaged girls with SLE from Japan (125505.0001). The nonsense mutations were associated with reduced DNASE activity and extremely high immunoglobulin G titer against nucleosomal antigens. Yasutomo et al. (2001) suggested that their data were consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE.

Blanco et al. (2001) hypothesized that SLE may be caused by alterations in the functions of dendritic cells. Consistent with this, monocytes from the blood of SLE patients were found to function as antigen-presenting cells in vitro. Furthermore, serum from SLE patients induced normal monocytes to differentiate into dendritic cells. These dendritic cells could capture antigens from dying cells and present them to CD4-positive T cells. The capacity of SLE patients' serum to induce dendritic cell differentiation correlated with disease activity and depended on the actions of interferon-alpha (147660). Thus, Blanco et al. (2001) concluded that unabated induction of dendritic cells by interferon-alpha may drive the autoimmune response in SLE.

Using a rheumatoid factor (RF+) transgenic B cell hybridoma line originally isolated from an autoimmune MRL/lpr mouse used as a model for SLE, Leadbetter et al. (2002) determined that these cells respond only to IgG2a immune complexes containing DNA and not to haptens or proteins. After ruling out complement receptors (i.e., CD21/CR2, 120650) as a potential second receptor on B cells, screening of cells expressing the adaptor protein Myd88 (602170), through which all toll-like receptors signal, revealed that RF+ B cells lacking Myd88 are completely unresponsive to IgG2a antinucleosome monoclonal antibodies (mAb). TLR9 (605474) responsiveness to CpG oligodeoxynucleotides (ODN) is presumed to require endosome acidification. The response to stimulation of RF+ B cells by IgG2a mAb or CpG-ODN, but not by TLR2 (603028) or TLR4 (603030) agonists, was blocked by inhibitors of endosome acidification, notably chloroquine, suggesting a mechanistic basis for its efficacy in the treatment for both RA and SLE. Leadbetter et al. (2002) proposed that other endogenous subcellular nucleic acid-protein autoantigens may signal through other TLRs to abrogate peripheral B-cell tolerance. They also suggested that infectious agent PAMP (patterns associated with microbial pathogens) engaging TLRs may create a synergy with autoantibody-autoantigen immune complexes, thus explaining the association between infection and autoimmune disease flares.

Risk of SLE is higher in people of West African descent than in Europeans. Molokhia et al. (2003) attempted to distinguish between genetic and environmental explanations for this ethnic difference by examining the relationship of disease risk to individual admixture (defined as the proportion of the genome that is of West African ancestry). They studied 124 cases of SLE and 219 matched controls resident in Trinidad. Analysis of admixture was restricted to 52 cases and 107 controls who reported no Indian or Chinese ancestry. These individuals were typed with a panel of 26 SNPs and 5 insertion/deletion polymorphisms chosen to have large allele frequency differentials between West African, European, and Native American populations. Mean West African admixture was 0.81 in cases and 0.74 in controls (P = 0.01). The risk ratio for SLE associated with unit change in this admixture was estimated as 32.5. Adjustment for measures of socioeconomic status (household amenities in childhood and years of education) altered this risk ratio only slightly. These results supported an additive genetic model for the ethnic difference in risk of SLE between West Africans and Europeans, rather than an environmental explanation or an 'overdominant' model in which risk is higher in heterozygous than in homozygous individuals.

Kowal et al. (2006) demonstrated that human anti-NMDA receptor antibodies isolated from patients with neuropsychiatric lupus caused hippocampal neuron damage and memory deficits when administered to mice with lipopolysaccharide to penetrate the blood-brain barrier. Postmortem brain tissue from 5 patients with neuropsychiatric lupus showed endogenous IgG that bound DNA and colocalized with NMDA receptor antibodies for NR2A (GRIN2A; 138253) and NR2B (GRIN2B; 138252). The findings suggested that some patients with neuropsychiatric lupus have circulating anti-NMDAR antibodies capable of causing neuronal damage and memory deficits if they breach the blood-brain barrier.

To examine the role of defensins in SLE pathogenesis, Sthoeger et al. (2009) used ELISA and real-time PCR to measure the levels of the alpha-defensin DEFA2 (125220) and the beta-defensin HBD2 (DEFB4; 602215) in the blood of SLE patients. They found that HBD2 was undetectable in sera from SLE patients, and that HBD2 mRNA was low in whole blood from SLE patients, similar to controls. In contrast, DEFA2 levels were significantly higher in all SLE patients compared with controls, and 60% of patients had very high serum levels. High DEFA2 levels correlated with disease activity, but not with neutrophil numbers, suggesting that neutrophil degranulation may lead to alpha-defensin secretion in SLE patients. Reduction of DEFA2 levels to the normal range correlated with disease improvement.

Kshirsagar et al. (2014) reported that enhanced STAT3 (102582) activity in CD4 (186940)-positive/CD45A (see 151460)-negative/FOXP3 (300292)-negative and FOXP3-low effector T cells from children with lupus nephritis (LN) correlated with increased frequency of IL17 (603149)-producing cells within these T-cell populations. Rapamycin treatment reduced both STAT3 activation and Th17 cell frequency in lupus patients. Th17 cells from children with LN exhibited high AKT (164730) activity and enhanced migratory capacity. Inhibition of AKT in cells from LN patients resulted in reduced Th17-cell migration. Kshirsagar et al. (2014) concluded that the AKT signaling pathway plays a significant role in Th17-cell migratory activity in children with LN. They suggested that inhibition of AKT may result in suppression of chronic inflammation in LN.

Excess Lymphocyte Low Molecular Weight DNA
Mackie et al. (1987) found circulating anticoagulants in multiple members of SLE families, but also found coagulation abnormalities in some spouses, suggesting that a transmissible agent or other environmental factors may be involved. All patients with SLE show 2 classes of newly synthesized DNA in sucrose density gradients of phytohemagglutinin-stimulated lymphocytes: a large-molecular-weight fraction that comigrates with control DNA and an excess low molecular weight DNA (LMW-DNA) fraction not found in control lymphocytes.

▼ Animal Model
Knight and Adams (1978) identified 2 genes in New Zealand white (NZW) mice that determine development of nephritis in crosses with New Zealand black (NZB) mice.

Theofilopoulos and Dixon (1985) provided a review of murine models of SLE.

F1 hybrids of NZB and NZW mice are a model of human SLE. These mice develop a severe immune complex-mediated nephritis, in which antinuclear autoantibodies seem to play a major role. Vyse et al. (1996) used a genetic analysis of a backcross between F1 hybrid mice and NZW mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin. These loci overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a locus on the distal part of mouse chromosome 4, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.

By linkage analysis, Morel et al. (1994) found that genomic intervals on mouse chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3) and 17 (Sle4) are strongly linked to lupus nephritis. Mohan et al. (1999) showed that on a normal B6 background, the introduction of Sle1, as in the monocongenic B6.NZMc1 mice, led to hyperglobulinemia, a breach in tolerance to chromatin, and a modest expansion of activated lymphocytes. However, serum autoantibodies did not target against double-stranded DNA or basement membrane antigens. When Sle1 and Sle3 were combined, as in the bicongenic B6.NZMc1/c7 mice, high titers of autoantibodies were generated which had specificity not only for the different chromatin epitopes (including dsDNA) but also for the intact glomeruli, leading to fatal lupus glomerulonephritis. These findings lent strong support to a 2-step epistatic model for the formation of pathogenic nephrophilic autoantibodies in lupus.

Gross et al. (2000) overexpressed BAFF (BLYS, or TNFSF13B; 603969) in lymphoid cells of transgenic mice and found that the mice develop symptoms characteristic of systemic lupus erythematosus and expand a rare population of splenic B-1a lymphocytes. Circulating BAFF was more abundant in New Zealand BWF1 and MRL lpr/lpr mice during the onset and progression of SLE. Gross et al. (2000) identified 2 TNF receptor family members, TACI (604907) and BCMA (109545), that bind BAFF. Treatment of New Zealand BWF1 mice with soluble TACI-Ig fusion protein inhibited the development of proteinuria and prolonged survival of the animals. These findings demonstrated the involvement of BAFF and its receptors in the develop of SLE and identified TACI/Ig as a promising treatment of autoimmune disease in humans.

Systemic lupus erythematosus is characterized by the presence of antinuclear antibodies (ANA) directed against naked DNA and entire nucleosomes. It was thought that the resulting immune complexes accumulate in vessel walls, glomeruli, and joints and cause a hypersensitivity reaction type III that manifests as glomerulonephritis, arthritis, and generalized vasculitis. Several studies had suggested that increased liberation or disturbed clearance of nuclear DNA-protein complexes after cell death may initiate and propagate the disease. Consequently, DNASE1 (125505), which is a major nuclease present in serum, urine, and secreta, may be responsible for the removal of DNA from nuclear antigens at sites of high cell turnover and thus prevent SLE. To test this hypothesis, Napirei et al. (2000) generated Dnase1-deficient mice by gene targeting. They found that these animals show the classic symptoms of SLE, namely the presence of ANA, the deposition of immune complexes in glomeruli, and full-blown glomerulonephritis in a Dnase1 dose-dependent manner. Moreover, in agreement with earlier reports, they found Dnase1 activities in serum to be lower in SLE patients than in normal subjects. The findings suggested that lack or reduction of Dnase1 is a critical factor in the initiation of human SLE.

Sun et al. (2002) reported that treatment with 2A, an agonistic monoclonal antibody to CD137 (TNFRSF9; 602250), blocked lymphadenopathy and spontaneous autoimmune disease in Fas-deficient mice (a model for human SLE), ultimately leading to their prolonged survival. Specifically, 2A treatment rapidly augmented interferon-gamma (IFNG; 147570) production and induced the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. Sun et al. (2002) concluded that agonistic monoclonal antibodies specific for costimulatory molecules could be used as novel therapeutic agents to deplete autoreactive lymphocytes and block autoimmune disease progression.

To clarify mechanisms governing the anxiety seen in lupus, Nakamura et al. (2003) carried out genomewide scans in mice and found that the region including interferon-alpha (IFNA; 147660) on chromosome 4 in NZB mice was significantly linked to the anxiety-like behavior seen in SLE-prone BWF1 mice. This finding was confirmed by anxiety-like performances of mice with heterozygous NZB/NZW alleles in the susceptibility region bred onto the NZW background. In BWF1 mice, neuronal IFN-alpha levels were elevated and blockade of the mu-1 opioid receptor (OPRM1; 600018) or corticotropin-releasing hormone receptor-1 (CRHR1; 122561), possible downstream effectors for IFN-alpha in the brain, partially overcame the anxiety-like behavior seen in these mice. Neuronal corticotropin-releasing hormone levels were consistently higher in BWF1 than NZW mice. Furthermore, pretreatment of mu-1 opioid receptor antagonist abolished anxiety-like behavior seen in IFN-alpha-treated NZW mice. Nakamura et al. (2003) concluded that a genetically determined endogenous excess amount of IFN-alpha in the brain may form 1 aspect of anxiety-like behavior seen in SLE-prone mice.

In SLE-prone NZB mice and their F1 cross with NZW mice, B cell abnormalities can be ascribed mainly to self-reactive CD5+ B1 cells. Li et al. (2004) performed a genomewide scan for susceptibility genes for aberrant activation of B1 cells in F1/NZB backcross mice and identified the Ltk gene as a possible candidate. Sequence and functional analyses of the gene revealed that NZB mice have a gain-of-function polymorphism in the LTK kinase domain near YXXM, a binding motif of the p85 subunit of phosphatidylinositol 3-kinase (PIK3R1; 171833). SLE patients had the equivalent human LTK polymorphism at a significantly higher frequency compared to healthy controls. Li et al. (2004) suggested that this LTK SNP may cause upregulation of the PI3K pathway and possibly form a genetic component of susceptibility to abnormal proliferation of self-reactive B cells in SLE.

Tournoy et al. (2004) reported that in PS1 (104311) +/- PS2 (600759) -/- mice, PS1 protein concentration was considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin (CTNNB1; 116806) downregulation. Their phenotype was normal up to 6 months, when the majority of the mice developed an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in human systemic lupus erythematosus. Besides B cell-dominated infiltrates, the authors observed a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The mice further developed a benign skin hyperplasia similar to human seborrheic keratosis (182000) as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts.

Despite the heterogeneity of factors influencing susceptibility to lupus, McGaha et al. (2005) demonstrated that the partial restoration of inhibitory Fc receptor (FC-gamma-RIIB; 604590) levels in B cells in lupus-prone mouse strains is sufficient to restore tolerance and prevent autoimmunity. Fc-gamma-RIIB regulates a common B-cell checkpoint in genetically diverse lupus-prone mouse strains, and modest changes in its expression can result in either tolerance or autoimmunity. McGaha et al. (2005) suggested that increasing Fc-gamma-RIIB levels in B cells may be an effective way to treat autoimmune diseases.

In the MRL-lpr mouse, Barber et al. (2005) found that pharmacologic inhibition of phosphoinositide 3-kinase-gamma (PIK3CG; 601232), a kinase that regulates inflammation, reduced CD4+ T-cell populations, reduced glomerulonephritis, and prolonged life span.

In both mice and humans with SLE, DeGiorgio et al. (2001) found that a subset of antibodies against dsDNA recognized portions of the extracellular domain of the NMDA receptor subunits, NR2A (138253) and NR2B (138252), which are present in the hippocampus, amygdala, and hypothalamus. Murine and human anti-dsDNA/anti-NR2 antibodies mediated apoptotic death of neurons in vitro and in vivo. Huerta et al. (2006) showed that mice immunized to produce anti-dsDNA/anti-NR2 IgG antibodies developed damage to neurons in the amygdala after being given epinephrine to induce leaks in the blood-brain barrier. The resulting neuronal insults were noninflammatory. Mice with antibody-mediated damage in the amygdala developed behavioral changes characterized by a deficient response to fear-conditioning paradigms. Huerta et al. (2006) postulated that when the blood-brain barrier is compromised, neurotoxic antibodies can penetrate the central nervous system and result in cognitive, emotional, and behavioral changes, as seen in neuropsychiatric lupus.

By inserting a region from the lupus-prone NZB mouse strain into an autoimmunity-resistant strain, Talaei et al. (2015) had previously found that a locus on chromosome 1 was associated with altered DC function and synergized with T-cell functional defects to promote expansion of pathogenic proinflammatory T-cell subsets. Talaei et al. (2015) showed that Eat2 (SH2D1B; 608510) was polymorphic in its promoter region in NZB mice, leading to a 70% reduction in Eat2 in DCs. Silencing of Eat2 in DCs lacking the NZB polymorphism resulted in increased Il12 (161560) production and enhanced differentiation of T cells into a Th1 phenotype, mimicking the DC phenotype in mice with the NZB polymorphism. Eat2 knockdown resulted in increased Il12 production by Cd40 (109535)-stimulated DCs. Talaei et al. (2015) concluded that EAT2 negatively regulates cytokine production in DCs downstream of SLAM (SLAMF1; 603492) engagement and that a genetic polymorphism disturbing this process promotes lupus development.

Bialas et al. (2017) reported behavioral phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signaling. Furthermore, the authors showed that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and the observation of increased type I IFN signaling in postmortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurologic symptoms observed in some patients with SLE.

▼ History
Fronek et al. (1986) found that the distribution of patterns of RFLPs at the T-cell receptor beta chain locus (see 186930) was the same in SLE patients as in their relatives and in controls. Thus, the authors concluded that the TCRB 'genes are not coinherited with genes responsible for' SLE. Wong et al. (1988) found no linkage to the alpha (see 186880), beta, and gamma (see 186970) genes of the T-cell receptor.

Levcovitz et al. (1988) reported a family in which a low-molecular-weight DNA marker for systemic autoimmune disease appeared to be inherited as an autosomal dominant trait; however, the report was later retracted.

Using flow cytometric analysis, Tao et al. (2005) found that NKT cells from patients with active SLE were more susceptible to apoptosis induced by anti-CD95 (TNFRSF6; 134637) than NKT cells from patients with inactive SLE or normal controls. Further analysis suggested that deficient expression of CD226 (605397) and survivin (BIRC5; 603352) in NKT cells from patients with active SLE may explain the sensitivity of these cells to apoptosis. However, in 2012, Tao et al. (2005) retracted their paper.

(文献)
for SLE
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