免疫グロブリンA1

関: IgA、IgA2、immunoglobulin A、immunoglobulin A1

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/18 22:02:23」(JST)

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The dimeric IgA molecule
1 H-chain
2 L-chain
3 J-chain

4 secretory component

IgA

Immunoglobulin A (IgA, also referred to as sIgA) is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined;^[1] between three and five grams are secreted into the intestinal lumen each day.^[2] This accumulates up to 15% of the total immunoglobulin produced in the entire body.^[3]

IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory IgA (sIgA). In its secretory form, IgA is the main immunoglobulin found in mucous secretions, including tears, saliva, sweat, colostrum and secretions from the genitourinary tract, gastrointestinal tract, prostate and respiratory epithelium. It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes, thus sIgA can survive in the harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions.^[4] sIgA can also inhibit inflammatory effects of other immunoglobulins.^[5] IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α.

Forms

IgA1 vs. IgA2

IgA exists in two isotypes, IgA1 and IgA2. They are both heavily glycosylated proteins.^[6] While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions);^[7] the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body:^[8]

IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA1-producing cells.^[9]
In IgA2, the heavy and light chains are not linked with disulfide, but with noncovalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue, or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes).

Both IgA1 and IgA2 have been found in external secretions like colostrum, maternal milk, tears and saliva, where IgA2 is more prominent than in the blood.^[7] Polysaccharide antigens tend to induce more IgA2 than protein antigens.^[8]

Serum vs. secretory IgA

It is also possible to distinguish forms of IgA based upon their location - serum IgA vs. secretory IgA.

In secretory IgA, the form found in secretions, polymers of 2-4 IgA monomers are linked by two additional chains; as such, the molecular weight of slgA is 385,000D. One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells.

The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called the secretory component that is produced by epithelial cells. This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.

IgA activity

The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that express an immunoglobulin receptor called the polymeric Ig receptor (pIgR). pIgA is released from the nearby activated plasma cells and binds to pIgR. This results in transportation of IgA across mucosal epithelial cells and its cleavage from pIgR for release into external secretions.^[10]

In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions.^[10] Ligation of FcαRI by IgA containing immune complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils, phagocytosis by monocytes, macrophages, and neutrophils, and triggering of respiratory burst activity by polymorphonuclear leukocytes.^[10]

SIgA primarily acts by blockading epithelial receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion.^[11] Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound to sterically hinder access to the epithelium.^[11]

Immune exclusion is a process of agglutinating polyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing them peristaltically. The oligosaccharide chains of sIgA’s secretory component can associate with the mucus layer that sits atop epithelial cells.^[11]

Production of sIgA against specific antigens depends on sampling of M cells and underlying dendritic cells, T cell activation, and B cell class switching in GALT, mesenteric lymph nodes, and isolated lymphoid follicles in the small intestine.^[11]

Transport

Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the secretory component, are free to diffuse throughout the lumen.^[12] In the gut, it can bind to the mucus layer on top of the epithelial cells to form a barrier capable of neutralizing threats before they reach the cell.

Clearance of IgA is mediated at least in part by asialoglycoprotein receptors, which recognizes galactose-terminating IgA N-glycans.^[13]

Pathology

Genetic

Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant immunodeficiency.

microbial

Neisseria species including Neisseria gonorrhœae (which causes gonorrhea),^[14] Streptococcus pneumoniae,^[15] and Haemophilus influenzae type B^[16] all release a protease which destroys IgA.

autoimmune/immune-mediated

IgA nephropathy is caused by IgA deposits in the kidneys. It is not yet known why IgA deposits occur in this chronic disease. Some theories suggest an abnormality of the immune system results in these deposits.^[17]

Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies.^[18]^[19]

Henoch–Schönlein purpura (HSP) is a systemic disorder caused by deposits of IgA and complement component 3 (C3) in the small vessels. HSP occurs usually in small children and involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates.^[20]

Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.^[21]

drug-induced

Vancomycin can induce a linear IgA bullous dermatosis in some patients.

References

^ S Fagarasan and T Honjo (2003). "Intestinal IgA Synthesis: Regulation of Front-line Body Defenses". Nature Reviews Immunology 3 (1): 63–72. doi:10.1038/nri982. PMID 12511876.
^ P. Brandtzaeg, R. Pabst (2004). "Let's go mucosal: communication on slippery ground". Trends Immunology 25 (11): 570–577. doi:10.1016/j.it.2004.09.005. PMID 15489184.
^ AJ Macpherson and E Slack. (2007). "The functional interactions of commensal bacteria with intestinal secretory IgA.". Current Opinion in Gastroenterology 23 (6): 673–678. doi:10.1038/nrmicro2114. PMID 17906446.
^ Junqueira, Luiz C.; Jose Carneiro (2003). Basic Histology. McGraw-Hill. ISBN 0-8385-0590-2.
^ Holmgren, J; Czerkinsky, C (April 2005). "Mucosal immunity and vaccines". Nature Medicine 11 (4s): S45–S53. doi:10.1038/nm1213. PMID 15812489.
^ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.
^ ^a ^b Delacroix, DL; Dive, C; Rambaud, JC; Vaerman, JP (Oct 1982). "IgA subclasses in various secretions and in serum.". Immunology 47 (2): 383–5. PMC 1555453. PMID 7118169.
^ ^a ^b Simell, B; Kilpi, T; Käyhty, H (Mar 2006). "Subclass distribution of natural salivary IgA antibodies against pneumococcal capsular polysaccharide of type 14 and pneumococcal surface adhesin A (PsaA) in children". Clinical and experimental immunology 143 (3): 543–9. doi:10.1111/j.1365-2249.2006.03009.x. PMC 1809616. PMID 16487254.
^ http://www.nature.com/mi/journal/v1/n1/pdf/mi20076a.pdf
^ ^a ^b ^c Snoeck V, Peters I, Cox E (2006). "The IgA system: a comparison of structure and function in different species". Vet. Res. 37 (3): 455–67. doi:10.1051/vetres:2006010. PMID 16611558.
^ ^a ^b ^c ^d Mantis, Nicholas, Rol, Nicolas, Corthésy, Blaise (Nov 2011). "Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut". Mucosal Immunology 4 (6): 603–11. doi:10.1038/mi.2011.41. PMC 3774538. PMID 21975936.
^ CS Kaetzel, JK Robinson, KR Chintalacharuvu, JP Vaerman, and ME Lamm (1991). "The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA". Proc Natl Acad Sci USA 88 (19): 8796–8800. doi:10.1073/pnas.88.19.8796. PMC 52597. PMID 1924341.
^ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMID 25578468.
^ Halter, R; Pohlner, J; Meyer, TF (Jul 1984). "IgA protease of Neisseria gonorrhoeae: isolation and characterization of the gene and its extracellular product". The EMBO Journal 3 (7): 1595–601. PMC 557564. PMID 6430698.
^ Proctor, M; Manning, PJ (Sep 1990). "Production of immunoglobulin A protease by Streptococcus pneumoniae from animals". Infection and immunity 58 (9): 2733–7. PMC 313560. PMID 2117567.
^ St Geme, JW 3rd; de la Morena, ML; Falkow, S (Oct 1994). "A Haemophilus influenzae IgA protease-like protein promotes intimate interaction with human epithelial cells". Molecular microbiology 14 (2): 217–33. doi:10.1111/j.1365-2958.1994.tb01283.x. PMID 7830568.
^ IgA Nephropathy on eMedicine
^ Prince, HE; Norman, GL; Binder, WL (Mar 2000). "Immunoglobulin A (IgA) deficiency and alternative celiac disease-associated antibodies in sera submitted to a reference laboratory for endomysial IgA testing". Clinical and diagnostic laboratory immunology 7 (2): 192–6. doi:10.1128/cdli.7.2.192-196.2000. PMC 95847. PMID 10702491.
^ Cunningham-Rundles C (Sep 2001). "Physiology of IgA and IgA deficiency". J. Clin. Immunol. 21 (5): 303–9. doi:10.1023/A:1012241117984. PMID 11720003.
^ Rai, A; Nast, C; Adler, S (Dec 1999). "Henoch-Schönlein purpura nephritis". J Am Soc Nephrol. 10 (12): 2637–44. PMID 10589705.
^ He Y, Shimoda M, Ono Y, Villalobos IB, Mitra A, Konia T, Grando SA, Zone JJ, Maverakis E (2015). "Persistence of Autoreactive IgA-Secreting B Cells Despite Multiple Immunosuppressive Medications Including Rituximab". JAMA Dermatol 151 (6): 646–50. doi:10.1001/jamadermatol.2015.59. PMID 25901938.

External links

Immunoglobulin A at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. IgGの構造および生物学的機能 structure and biologic functions of iga
2. IgA腎症の治療および予後 treatment and prognosis of iga nephropathy
3. 選択的IgA欠損症：臨床症状、病態生理、および診断 selective iga deficiency clinical manifestations pathophysiology and diagnosis
4. IgA腎症の臨床症状および診断 clinical presentation and diagnosis of iga nephropathy
5. 選択的IgA欠損症：管理および予後 selective iga deficiency management and prognosis

English Journal

Nasal fluid secretory immunoglobulin A levels in children with allergic rhinitis.

Dilek F1, Ozkaya E2, Gultepe B3, Yazici M2, Iraz M3.
International journal of pediatric otorhinolaryngology.Int J Pediatr Otorhinolaryngol.2016 Apr;83:41-6. doi: 10.1016/j.ijporl.2016.01.018. Epub 2016 Jan 28.
OBJECTIVES: There is growing knowledge about the immunoregulatory and possibly preventative roles of immunoglobulin A (IgA) in allergic diseases. This study aimed to investigate secretory immunoglobulin A (SIgA) levels in the nasal fluid of children who were either being treated for their allergic r
PMID 26968051

Rapamycin, a specific inhibitor of the target of rapamycin complex 1, disrupts intestinal barrier integrity in broiler chicks.

Liu SQ1, Zhao JP1, Fan XX1, Liu GH1, Jiao HC1, Wang XJ1, Sun SH1, Lin H1.
Journal of animal physiology and animal nutrition.J Anim Physiol Anim Nutr (Berl).2016 Apr;100(2):323-30. doi: 10.1111/jpn.12375. Epub 2015 Aug 6.
To uncover the molecular mechanisms underlying the intestinal barrier integrity, this study determined whether the rapamycin (RAPA)-sensitive target of rapamycin complex 1 (TORC1) pathway was involved in this process. Three groups of 4-day-old male chicks were randomly subjected to one of the follow
PMID 26249793

Positive Reinforcement Training for Blood Collection in Grizzly Bears (Ursus arctos horribilis) Results in Undetectable Elevations in Serum Cortisol Levels: A Preliminary Investigation.

Joyce-Zuniga NM1,2, Newberry RC2,3,4, Robbins CT5, Ware JV4, Jansen HT4, Nelson OL1,2.
Journal of applied animal welfare science : JAAWS.J Appl Anim Welf Sci.2016 Apr-Jun;19(2):210-5. doi: 10.1080/10888705.2015.1126523. Epub 2016 Feb 4.
Training nonhuman animals in captivity for participation in routine husbandry procedures is believed to produce a lower stress environment compared with undergoing a general anesthetic event for the same procedure. This hypothesis rests largely on anecdotal evidence that the captive subjects appear
PMID 26847149

Japanese Journal

Henoch-schönlein purpura nephritis in childhood: pathogenesis, prognostic factors and treatment

Kawasaki Yukihiko,Ono Atsushi,Ohara Shinichiro,Suzuki Yuichi,Suyama Kazuhide,Suzuki Junzo,Hosoya Mitsuaki
Fukushima Journal of Medical Science 59(1), 15-26, 2013
… As to the pathogenesis, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, thereby inducing renal injury. …
NAID 130003376082

慢性腎臓病と透析医療 : 研究の歩みから腎の再生医療に向けて

成田一衛,斎藤亮彦,下條文武
再生医療 : 日本再生医療学会雑誌 11(1), 35-50,105, 2012-02
NAID 40019180935

P2-104 膠原病に伴う間質性肺炎患者におけるIgAサブクラス，BAFF/APRILの関与について

金子俊之,天野浩文,河野晋也,箕輪健太郎,安藤誠一郎,渡邉崇,仲野総一郎,鈴木淳,森本真司,髙崎芳成
日本臨床免疫学会会誌 35(4), 378b-378b, 2012
… MCTDを中心とする膠原病患者63人を間質性肺炎合併群（IP+）20人と間質性肺炎非合併群（IP−）43人に分け，血清中のIgA1, IgA2値（DID法）とBAFF・APRIL値（ELISA法）を測定した．さらに患者血清を用いてフローサイトメトリー（FACS）でBAFFに関与するレセプターの測定を行った． …
NAID 130003364138

Related Pictures

★リンクテーブル★

リンク元	「IgA腎症」「IgA血管炎」「IgA2」「免疫グロブリンA1」「immunoglobulin A1」
関連記事	「IgA」「Ig」

「IgA腎症」

　　[★]

英: IgA nephropathy, immunoglobulin A nephrophathy
同: IgAメサンギウム腎症 IgA mesangial nephropathy、免疫グロブリンA腎症イムノグロブリンA腎症 immunoglobulin A nephropathy、IgA腎炎 IgA nephritis、IgA糸球体腎炎 IgA glomerulonephritis、Berger's disease、バージャー病ベルガー病ベルジェ病 Berger's disease Berger disease Berger病 Berger nephropathy
関: 一次性糸球体疾患。

[show details]

バージャー病 : 約 101,000 件
ベルガー病 : 38 件
ベルジェ病 : 約 12,300 件
バージャー病 Berger : 約 35 件
ベルガー病 Berger : 8 件
ベルジェ病 Berger : 40 件

first aid step1 2006 p.385(Glomerular pathology)

定義

原発性糸球体腎炎のうち，メサンギウムを中心とするIgA(IgA1)沈着が優位な増殖性糸球体腎炎。慢性糸球体腎炎の一型
一次性、または特発性であること

→ 同様の症状を示す、紫斑病性腎炎(Henoch-Schonlein purpura)、肝硬変、肺疾患とは区別する！！

疫学

日本－原発性糸球体腎炎の50-70％ (約40%とする文献もある)。フランス－原発性糸球体腎炎の約20％
発症年齢：小児から成人まで認められる。20歳代に好発。男性が若干多い(男女比 3-6：1)
若年の新規透析患者の原因(約40%)として重要である。　→　透析導入原疾患の第2位
慢性糸球体腎炎のなかで最多(約半数)。

病因

免疫複合体型腎炎
IgAを含む免疫複合体が糸球体に沈着し　→　補体を活性化　→　腎炎

抗原：細菌、ウイルス、食物蛋白など
begin as an episode of gross hematuria that occurs within 1 or 2 days of a nonspecific upper respiratory tract infection

病態

抗原と結合したIgAからなる免疫複合体が糸球体内皮下とメサンギウム領域に蓄積し腎炎像がみられる。(PRE.245)　　→　　炎症により部分的に糸球体が破綻し血尿をきたす？

糸球体腎炎症状が主であって、蛋白尿は軽度。ネフローゼに至ることは稀

病理

メサンギウム増殖性糸球体腎炎の像が見られる。
光学顕微鏡：メサンギウム増殖
蛍光顕微鏡：IgAが顆粒状にメサンギウムに沈着。C3, IgG, IgMの沈着が見られることがある

[show details]

メサンギウムにIgAが沈着する疾患

検査

免疫血清学的検査

IgA：高値
血清補体価：正常

尿検査：

蛋白尿は血尿に比べ軽度　　←　　ネフローゼ優位ではない？

血尿：顕微鏡的、肉眼的(高頻度。1/3の例らしい)。
尿タンパク：陽性(70%。1g/day以下の例が多い)
尿沈渣：進行例では赤血球円柱、白血球円柱、顆粒円柱、硝子円柱が増加していき、ネフローゼ症候群に至れば卵円形脂肪体が出現。

診断

腎生検が確定診断のための唯一の検査

鑑別診断

IgA腎症、紫斑病性腎炎(ヘノッホ・シェーンライン紫斑病性腎炎)、ループス腎炎　→　いずれもIgAがメサンギウムに沈着する

治療

参考2

1. ACE阻害薬、アンジオテンシン受容体阻害薬
2. 糖質コルチコイド
3. 免疫抑制薬

SPE.596

組織障害が軽い例：抗血小板薬、柴苓湯、ACE阻害薬、ARB
組織障害が強い例：副腎皮質ステロイド、抗凝固薬、抗血小板薬、免疫抑制薬の組み合わせ。

予後

著明な蛋白尿や腎機能低下をきたさない患者は完全に寛解するかもしれないが、ほとんどの患者ではゆっくり着実に進行する。
蛋白尿の持続　±　高血圧　±　血清Crの上昇　を下している患者は20年の経過で20-30%が末期腎不全に陥り、そのほかの20%は腎機能が低下する。
予後不良の腎組織像は、(稀)半月体の形成、糸球体の瘢痕化、尿細管質の萎縮、および間質の線維化である。

予後予測因子

YN.E-43

血圧＞160/95 mmHg、血清Cr＞1.5 mg/dL、Ccr＜50、尿蛋白＞2g/日

予後不良因子

蛋白尿の持続、高血圧、高血清Cr、血清蛋白低値、高度な腎組織障害

参考

1.IgA腎症診療指針－第2版－

http://www.jsn.or.jp/jsn_new/iryou/free/kousei/pdf/44_7.pdf

2. [charged] Treatment and prognosis of IgA nephropathy - uptodate [1]

国試

105A046、098A036

[show details]

「IgA血管炎」

　　[★]

英: IgA vasculitis IgAV
同: アナフィラクトイド紫斑病、ヘノッホ・シェーンライン紫斑病 Henoch-Schönlein purpura, Henoch-Schonlein purpura, HSP, Schonlein-Henoch purpura, Schonlein-Henoch purpura; ヘノッホ・シェンライン紫斑病、Henoch-Schonlein紫斑病、Henoch-Schonlein紫斑、シェンライン・ヘノッホ紫斑病、シェーンライン・ヘノッホ紫斑病、Schonlein-Henoch紫斑病; アナフィラキシー様紫斑病アナフィラクトイド紫斑病アナフィラクトイド紫斑、anaphylactoid purpura、アレルギー性紫斑病アレルギー性紫斑 allergic purpura purpura allergica、アレルギー性血管炎 allergic vasculitis、リウマチ性紫斑病 rheumatic purpura purpura rheumatica、ヘノッホ紫斑病
関: IgA腎症。血管性紫斑病、皮膚小血管性血管炎、血管炎、劇症紫斑病、血小板非減少性紫斑病

まとめ

先行する上気道感染後に出現する紫斑が特徴的な血管炎である。IgAによる免疫複合体の血管壁への沈着、およびこれに次いで起こるIII型アレルギーが本態と考えられている。症状はG²AP、すなわち消化管症状、糸球体腎炎、関節痛、紫斑である。血液検査では軽度の好中球増多・好酸球増多がみられ、血液中のIgAも上昇するが、血小板、補体、IgG,IgEは変化しない。