Complement functions اپسونیزاسیون و فاگوسیتوز تحریک پاسخ های التهابی

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Complement functions اپسونیزاسیون و فاگوسیتوز تحریک پاسخ های التهابی سیتولیز پاکسازی کمپلکسهای ایمنی و سلولهای مرده تسهیل فعال سازی سلولهای B و شروع پاسخ های ایمنی هومورال

سيستم كمپلمان شامل پروتئينهاي پلاسمايي و غشايي مي باشد كه با يكديگر و با ساير مولكولهاي سيستم ايمني واكنش مي دهند اين سيستم بوسيله ميكروبها و يا آنتي باديهايي كه به ميكروبها وساير آنتي ژنهاچسبيده اندفعال مي شود فعال شدن اين سيستم بوسيله پروتئينهاي تنظيمي كه در سطح سلولهاي طبيعي ميزبان وجود دارند مهارمي شود

Pathways of complement activation CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY

Components of the Classical Pathway C1r C1s C1q C4 C2 C3 Chelating agents dismantle the C1 complex and are anti-complementary. Heat destroys the C2 component. Sample for C measurement should be drawn in a green-top vial (no EDTA), must be kept cold and tested as soon as possible. C1 complex

Classical Pathway Generation of C3-convertase b Ca++ C1r C1s C1q C4

Classical Pathway Generation of C3-convertase C2b a C4a Ca++ C1r C1s C1q _____ C4b2a is C3 convertase Mg++ C4b

Classical Pathway Generation of C5-convertase C2b C4a Ca++ C1r C1s C1q C3a b ________ C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Mg++ C4b C3 C2 a

Generation of C5 convertase leads to the activation of the Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway

Components of the lytic pathway 9

Lytic pathway C5-activation b C5a C5 C3b C4b C2 a

Lytic pathway assembly of the lytic complex

Lytic pathway: insertion of lytic complex into cell membrane 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9

Components of mannose-binding lectin pathway MASP2 C2 MASP1 MBL

Mannose-binding lectin pathway _____ C4b2a is C3 convertase; it will lead to the generation of C5 convertase C4b C4a C2b C2a C4b C4 C2a C2 MASP2 MASP1 MBL

لكتينهاي پلاسمايي مثل MBL وفيكولين ها به پلي ساكاريدهاي غشايي باكتريها باند مي شوند و سيستم كمپلمان بطريق كلاسيك فعال مي شود MBL به مانوز و فيكولين به گليكانهايي كه حاوي ان-استيل گلوكزآمين هستندباند مي شوند اين لكتينها به سرين پروتئازهاي مثل MASP1,MASP2,MASP3 باند مي شوند اين مولكولهاي MASP شبيه به C1r و C1s هستند

PTXs + C1q complement activation Binding to C1q Receptors on phagocytes opsonization

Components of the alternative pathway D C3 B P

Spontaneous C3 activation Generation of C3 convertase D b i H2O B C3a b C3 C3 C3iBb complex has a very short half life

C3-activation the amplification loop If spontaneously-generated C3b is not degraded b D B C3a b C3b C3

C3-activation the amplification loop b D B C3a b C3b C3 Bb C3b C3a

C3-activation the amplification loop b D Bb B b C3a C3b C3b C3 Bb C3b C3a C3a

C3-activation the amplification loop Bb Bb C3b C3b C3b Bb C3b C3a C3a C3a

C3-activation the amplification loop Bb Bb C3b C3b Bb C3b C3a C3a C3a

Regulation of complement activation براي جلوگيري از فعاليت كمپلمان روي سلولهاي طبيعي ميزبان و براي محدود كردن مدت فعاليت كمپلمان حتي روي سلولهاي ميكروبي و كمپلكسهاي Ag-Ab اين مكانيسمهاي كنترلي و تنظيمي نياز است

Regulatory mechanisms تنظیم و کنترل فعالیت سیستم کمپلمان در مراحل مختلفی (از ابتدا تا انتهای فعالیت) برروی سلولهای میزبان صورت می گیرد. 1-مهار شروع فعالیت سیستم 2-مهار تشکیل C3کنورتازها 3- شکستن یا غیر فعال سازی کنورتازها 4-مهار تشکیل کمپلکس حمله به غشاء

انواع مولکولهای کنترلی C1INH Membrane cofacto protein(MCP) Complement receptor-1(CR-1) Decay accelerating factor(DAF) factor H C4-binding protein(C4bp) CD59 Factor I S-protein

C1-Inhibitor C1INH یک پروتئین پلاسمایی است که در ابتدای فعالیت سیستم عمل می کند.این پروتئین نقش سوبسترای C1r و C1s راتقلید کرده وپس از اتصال C1q به آنتی بادی وشروع فعالیت سیستم کمپلمان C1INH تحت اثر آنزیم های C1r وC1r شکسته می شود وبطور کووالانس به این پروتئین ها متصل می شودو باعث جداسازی این پروتئینها از C1q می گرددوبنابر این مانع پیشرفت فعالیت سیستم بطریق کلاسیک می شود

ممانعت از تشکیل کنورتاز ها چنانچه C3b روی سطوح سلولهای میزبان بنشیندممکن است بوسیله چندین پروتئین غشایی مثل MCP,CR-1,DAF ویک پروتئین پلاسمایی بنام فاکتور H متصل شود C4b در سطح سلولهای میزبان بطور مشابه بوسیله DAF و CR-1 ویک پروتئین پلاسمایی بنام C4bp متصل می شوند با اتصال این پروتئین ها به C3b و C4b ، بطور رقابتی مانع از اتصال سایر قطعات C3 کنورتاز مثل Bb درمسیر فرعی و C2a درمسیر کلاسیک می شودوبنابراین مانع از پیشرفت آبشار کمپلمان می گردد. وجود سیالیک اسید در سطح سلولهای پستانداران بنفع اتصال فاکتور H به فاکتور B است

DAF یک پروتئین غشایی است که با واسطه گلیکوفسفاتیدیل اینوزیتول به غشاء سلول های اندوتلیال و اریتروسیتها متصل است. نقص ژنتیکی درآنزیمی که برای چنین اتصال لیپید-پروتئین نیاز است منجر به نقص در بیان بسیاری ازپروتئینهایی مثل DAF وCD59 میشودوبنابراین موجب بیماری paroxysmal nocturnal hemoglobinuria(PNH) شده که ازمشخصه آن همولیز داخل عروقی است که می تواند ناشی از عدم تنظیم فعالیت کمپلمان روی گلبولهای قرمز باشد.

مهار تشکیل MAC CD59 پروتئین غشایی است که روی بسیاری ازانواع سلولها بیان می شوداین پروتئین خودرا بداخل کمپلکس MAC وارد می کندیعنی به کمپلکس C5b678 که درون غشاء فرورفته متصل شده و مانع از اضافه شدن مولکولهای C9 می گردد. پروتئین S در پلاسما با اتصال به کمپلکس C5b67 محلول ،مانع از فرورفتن این کمپلکس به داخل غشاء سلول ها می گردد

Control of spontaneous C3 activation via DAF DAF prevents the binding of factor B to C3b C3b B Autologous cell membrane DAF CR1

Control of spontaneous C3 activation via DAF DAF dislodges C3b-bound factor Bb B b B b C3b Autologous cell membrane DAF CR1

Control of spontaneous C3 activation via CR1 B b C3b B b H C3b iC3b DAF CR1 I iC3b DAF I CR1 Autologous cell membrane

C5-convertase of the two pathways C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway Bb C4b C2a C3b C3b C3b

Complement Receptors CR-I(CD35) promote phagocytosis اين گيرنده در سطح نوتروفيلها ، اريتروسيت ها ، منوسيتها و ماكروفاژها، ائوزينوفيلها و .. بيان مي شود.ليگاند آن C3b وC4b مي باشد CR-II(CD21) coreceptor for B cell activation ليگاند اين گيرنده C3d و C3dg CR-III (Mac-1) phagocytosis اين گيرنده در سطح سلولهاي فاگوسيت ، ماست سلها و سلولهاي NK بيان مي شود وليگاند آنiC3b مي باشد.اين گيرنده ازگروه اينتگرينها مي باشند CR-IV phagocytosis شبيه به گيرنده سوم مي باشد .

Biological properties of C-activation products Biological Effects Regulation C3b (opsonin) opsonization; phagocyte activation factors H & I as C3, but less potent (C3-INA) C4a (anaphylatoxin) opsonization; phagocytosis C4b (opsonin) C4-BP, factor I

Biological properties of C-activation products Biological Effects Regulation anaphylactic as C3, but much more potent; attracts & activates PMN causes neutrophil aggregation, stimulation of oxidative metabolism and leukotriene release C5a (chemotactic factor) carboxy-peptidase-B (C3-INA) C5b67 protein-S chemotaxis, attaches to other membranes

Complement level سطح کمپلمان ممکن است در شرایط زیر کاهش یابد: الف) ارثی ب) اکتسابی 1) مصرف زیاد( عفونت های راجعه بویژه باکتریال، بیماریهای خودایمن مثل SLE ، آنژیوادم ، بیماریهای مختلف کلیوی ، سپتی سمی ، بیماری سرمی و ...) 2) کاهش تولید ( سوء تغذیه ، بیماریهای کبدی ) طی التهاب حاد یا مزمن همراه با پروتئین های فاز حاد سطح پروتئین های کمپلمان نیز افزایش می یابد. سیستم کمپلمان نقش مهمی در دفاع علیه باکتریهای پیوژن بازی می کند.این فعالیت بیشتر از طریق پیشبرد پاسخ های التهابی ، حذف پاتوژن ها وتقویت پاسخ های ایمنی صورت می گیرد. کمبود پروتئین های این سیستم می تواند به شیوع عفونت ها و سپتی سمی منجر شود.

The genetic deficiency of early components of the classical pathway (C1q, C1r/s, C2, C4) tend to be linked with autoimmune diseases whereas C5 to C9 may have enhanced susceptibilty to meningococcal disease. Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization (2) defects in lytic activity (defects in MAC).

Th e effects of these deficiencies highlight the importance of the early complement reactions in generating C3b and C3b’s role in the solubilization and clearance of immune complexes. In addition, C1q has been shown to bind apoptotic blebs. In the absence of C1q binding, cells bearing these apoptotic blebs, or the blebs themselves, can act as autoantigens and lead to the development of autoimmune diseases Individuals with deficiencies in the early complement components may also suffer from recurrent infections by pyogenic (pus-forming) bacteria such as streptococci and staphylococci

A deficiency in MBL, the first component of the lectin pathway, has been shown to be relatively common, and results in serious pyrogenic (fever-inducing) infections in babies and children. Children with MBL deficiency suffer from respiratory tract infections. People with C3 deficiencies display the most severe clinical manifestations of any of the complement deficiency patients, reflecting the central role of C3 in opsonization and in the formation of the MAC.