َّ ِ‫الر ْح ٰمن‬
َّ ‫للا‬
ِ‫الر ِح ْي ِم‬
ِِ ‫م‬
ِ ِ ‫ِب ْس‬
The Complement System (1)
History:
❑ Research on complement began in the 1890s, when
Jules Bordet at the Institut Pasteur in Paris showed that
sheep antiserum to the bacterium Vibrio cholerae
caused lysis of the bacteria and that heating the
antiserum destroyed its bacteriolytic activity.
❑ He named those substances as Alexins.
❑ Paul Ehrlich coined the term complement.
Introduction:
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Three main effects of complement are:
1. Lysis of cells (bacteria, allografts, tumor cells).
2. Generation of mediators of inflammation
3. Opsonization – enhancement of phagocytosis.
It is named “complement system” because it was first
identified as a heat-labile component of serum that
“complemented or augment (বৃদ্ধি)” antibodies in the
killing of bacteria.
Consists of serum and cell surface proteins involved in
defense against pathogens and tissue damage
mediated by antibodies
The Complement system is the major effector of
cellular and humoral branch of immune system.
Plays major role in both innate and adaptive
immunity.
Complement system represents a group of about 30
proteins which augment or complement the immune
response.
Most of these proteins are found in serum or on cell
surfaces.
Synthesized in liver as inactive precursors and are
activated by proteolysis during their interaction in a
sequential manner.
Also produced by blood monocytes, tissue
macrophages and epithelial cells of the
gastrointestinal and genitourinary tract.
General Properties:
 Present in serum of all animals but its concentration
is maximum in serum of guinea pig.
 Complement of one species are able to react with
antibodies of other species but not to the same
extent.
 C- proteins constitute about 5% of normal serum
protein.
 Are glycoproteins.
Department of Pharmacy
 Are synthesized rapidly in inflammatory responses –
hence are called acute phase proteins.
 Heat labile (পরিবর্তনশীল) and lost activity at 56⁰ C for
30 mins and inactivated. Immunoglobulins are not
inactivated at this temperature.
 Binds with Fc potion of immunoglobulins.
System:
Over 30 serum and cell surface proteins:
➢ Complement components.
 Components are designated by numbers (E.g.; C1
– C9) or latter’s (E.g.: Factor D).
 (in serum inactive, activated sequentially as a
cascade).
➢ Complement receptors.
 (cell surface, recognize activated components).
➢ Regulatory proteins of complement.
 (both in serum and cell surface, inhibit activated
components).
➢ Complement proteins: are proenzymes - activation by
cleavage.
➢ Example:
Figure 1: a = smaller fragment. -Diffusion. b= larger fragment. remains bound to microbe.
➢ Exception: C2: C2a = large fragment, C2b = small
fragment.
Complement Pathway:
Three pathway of complement activation
1) Classical pathway: Is antibody dependent pathway and triggered by formation
of soluble antigen-antibody complex or by binding of the
antibody to the antigen present on the target cell surface.
Immunology
Page 1 | 8
আবু হুরায়রা (রাাঃ) থেকে বর্ণত
ি র্তর্ি বকেি, রাসূেুল্লাহ্‌সাল্লাল্লাহু আোইর্হ ওয়া সাল্লাম বকেকেি:ِ“রমযাকির পর সবকেকয় উত্তম থরাযা হকে- আল্লাহর
মাস ‘মুহররম’ এর থরাযা।” (সর্হহ মুসর্েম: ১৯৮২)
2) Alternative pathway: Is antibody independent pathway stimulated by antigen
directly eg. Bacterial cell surface components.
3) Lectin Pathway: Also, antibody independent but resembles classical
pathway.
Stages of Complement Activation:
Three main stages in the activation of complement by any
pathway is
◆ Formation of C3 convertase.
◆ Formation C5 convertase.
◆ Formation of membrane attack complex (MAC).
The initiation and formation of C3 convertase are different
in classical and alternative pathway. These then follow the
parallel route to merge at C5 convertase stage and finally
generate the MAC by a common route.
Sequential activation of complement components occurs
via one of three pathways:
 The classic pathway,
 The lectin pathway, and
 The alternative pathway.
❖ Of these pathways, the lectin and the alternative
pathways are more important the first time we are
infected by a microorganism because the antibody
required to trigger the classic pathway is not present.
❖ The lectin pathway and the alternative pathway are,
therefore, participants in the innate arm of the
immune system.
❖ All three pathways lead to the production of C3b, the
central molecule of the complement cascade.
❖ The presence of C3b on the surface of a microbe marks
it as foreign and targets it for destruction. C3b has two
important functions:
•
•
C-fixation: utilization of C by Ag-Ab complexes.
C-inactivation: denaturation (usually by heat) of an
early C-component resulting in loss of hemolytic
activity.
• Convertase/esterase: altered C-protein which acts as a
proteolytic enzyme for another C-component.
Classical Pathway:
 Part of acquired immunity.
 In the classic pathway, antigen–antibody complexes
activate C1 to form a protease, which cleaves C2 and
C4 to form a C4bC2a complex, C2a and C4b split off.
 The C4bC2a is C3 convertase, which cleaves C3
molecules into two fragments, C3a and C3b.
 C3b forms a complex with C4b,2b, producing a new
enzyme, C5 convertase (C4b2a3b), which cleaves C5 to
form C5a and C5b
 C5b binds to C6 and C7 to form a complex that
interacts with C8 and C9 to produce the membrane
attack complex (C5b,6,7,8,9), which causes cytolysis.
 Note that the "b" fragment continues in the main
pathway, whereas the "a" fragment is split off and has
other activities except C2a which binds and C2b which
 Only IgM and IgG fix complement.
 One molecule of IgM can activate complement;
however, activation by IgG requires two cross-linked
IgG molecules.
 Of the IgGs, only IgG1, IgG2, and IgG3 subclasses fix
complement; IgG4 does not.
 C1 is bound to a site located in the Fc region of the
heavy chain.
 C1 is composed of three proteins, C1q, C1r, and C1s.
 C1q is an aggregate of 18 polypeptides that binds to
the Fc portion of IgG and IgM.
 It is multivalent and can cross-link several
immunoglobulin molecules.
 C1s is a proenzyme that is cleaved to form an active
protease.
1. It combines with other complement components to
generate C5 convertase, the enzyme that leads to the
production of the membrane attack complex, and
2. It opsonizes bacteria because phagocytes have
receptors for C3b on their surface.
Some Definitions:
• C-activation: alteration of C proteins such that they
interact with the next component.
Figure 2
Edited by: Syed Salauddin Parvez, Third batch, Department of Pharmacy, MBSTU.
Page 2 | 8
র্িশ্চয়ই আল্লাহ্‌র োকে থতামাকের িামগুকোর মাকে সবকেকয় পেন্দিীয় হে 'আবেুল্লাহ্‌ও 'আবেুর রাহমাি’। [মুসর্েম]
Lytic Pathway:
Figure 3: C4b-2a-3b functions as the classical. C5 convertase.
Figure 6: Assembly of the Lytic Complex.
Figure 7: insertion of lytic complex into cell membrane.
Alternative Pathway:
Figure 4: Classical Pathway Generation of C3-convertase.
 Ab independent pathway.
 In the alternative pathway, many unrelated cell surface
substances, e.g., bacterial lipopolysaccharides
(endotoxin), fungal cell walls, and viral envelopes, can
initiate the process by binding C3 and factor B.
 This complex is cleaved by a protease, factor D, to
produce C3bBb.
 This acts as a C3 convertase to generate more C3b.
 Alternative pathways are more important the first time
we are infected by a microorganism.
 Usually activated by products of micro-organisms like
endotoxin.
Other activators include:
1. Complexes containing IgA.
2. Some virus-infected cells (e.g. EBV).
3. Many gram negative and gram positive organisms.
4. Parasites – Trypanosomes, Leishmania.
5. Erythrocytes.
6. Carbohydrates (agarose).
Figure 5: Classical Pathway Generation of C5-convertase.
Department of Pharmacy
Immunology
Page 3 | 8
আবু হুরায়রা (রাাঃ) থেকে বর্ণত
ি র্তর্ি বকেি, রাসূেুল্লাহ্‌সাল্লাল্লাহু আোইর্হ ওয়া সাল্লাম বকেকেি:ِ“রমযাকির পর সবকেকয় উত্তম থরাযা হকে- আল্লাহর
মাস ‘মুহররম’ এর থরাযা।” (সর্হহ মুসর্েম: ১৯৮২)
Lectin Pathway:
 Also known as the MBL Pathway.
 In the lectin pathway, mannan-binding lectin (MBL)
(also known as mannose-binding protein) binds to the
surface of microbes bearing mannan (a polymer of the
sugar, mannose).
 Binding causes activation of MASP (MBP- associated
serine proteases) → cleave C2 and C4 and activate the
classic pathway.
 Note that this process bypasses the antibody-requiring
step and so is protective early in infection before
antibody is formed.
Figure 9
Membrane Attack Complex:
 Cleavage of C5 into C5a and C5b.
 C5 (structurally homologous to C3 and C4, lacks
internal thioester bond).
 C5b initiates formation of MAC (complex of C5b, C6,
C7, C8 and multiple C9 molecules) binds to C6, and C7,
recruits C8 and complex penetrates more deeply into
the membrane.
 C9, a pore-forming molecule with homology to
perforin. The complex of C5b678 forms a nidus for C9
binding and polymerization.
 Penetrates membrane bilayers to form pores.
 Disrupt the osmotic barrier, leading to swelling and
lysis of susceptible cells.
Figure 8: Lectin Pathway.
Edited by: Syed Salauddin Parvez, Third batch, Department of Pharmacy, MBSTU.
Page 4 | 8
র্িশ্চয়ই আল্লাহ্‌র োকে থতামাকের িামগুকোর মাকে সবকেকয় পেন্দিীয় হে 'আবেুল্লাহ্‌ও 'আবেুর রাহমাি’। [মুসর্েম]
Biologic Effects of Complement:
Regulation of Complement System:
1. Opsonization
1. C1 inhibitor
 C3b & C1q; enhance phagocytosis.
2. Chemotaxis
 C5a and C5,6,7 complex → attract neutrophils.
 C5a – enhance adhesiveness of neutrophils to the
endothelium.
3. Anaphylatoxin (C3a, C4a, C5a)
 Cause degranulation of mast cells
 Bind directly to smooth muscles of bronchioles →
bronchospasm.
 Important regulator of classic pathway.
 A serine protease inhibitor (serpin).
 Irreversibly binds to and inactivates C1r and C1s, as
well as MASP in lectin pathway.
2. Factor H
 Regulate alternative pathway.
 Reduce amount of C5 convertase available.
 With both cofactor activity for the factor Imediated C3b cleavage, and decay accelerating
activity against C3bBb (C3 convertase).
3. Properdin
 Protects C3b and stabilizes C3 convertase.
4. Factor I
 Cleaves cell-bound or fluid phase C3b and C4b→
inactivates C3b and C4b.
5. Decay accelerating factor (DAF)
 Glycoprotein on surface of human cells.
 Prevents assembly of C3bBb or accelerates
disassembly of preformed convertase → no
formation of MAC.
 Acts on both classical and alternative.
6. C4b-binding protein (C4BP)
 Inhibits the action of C4b in classical pathway.
 Splits C4 convertase and is a cofactor for factor I.
Figure 10: C3b is an opsonin, Opsonin’s are molecules that bind both
to bacteria and phagocytes Opsonization increases phagocytosis by
1,000-fold.
4. Cytolysis (MAC)
7. Complement Receptor 1 (CR-1)
 Co-factor for factor I, together with CD46.
8. Protectin (CD59) and Vitronectin (S protein)
 Disrupt the membrane & the entry of water and
electrolytes into the cell.
5. Enhancement of antibody production
 Inhibits formation of MAC by binding C5b678.
 Present on “self” cells to prevent complement
from damaging them.
 Binding of C3b to its receptors on the surface of
activated B cells → enhanced antibody production.
Department of Pharmacy
Immunology
Page 5 | 8
আবু হুরায়রা (রাাঃ) থেকে বর্ণত
ি র্তর্ি বকেি, রাসূেুল্লাহ্‌সাল্লাল্লাহু আোইর্হ ওয়া সাল্লাম বকেকেি:ِ“রমযাকির পর সবকেকয় উত্তম থরাযা হকে- আল্লাহর
মাস ‘মুহররম’ এর থরাযা।” (সর্হহ মুসর্েম: ১৯৮২)
Edited by: Syed Salauddin Parvez, Third batch, Department of Pharmacy, MBSTU.
Page 6 | 8
র্িশ্চয়ই আল্লাহ্‌র োকে থতামাকের িামগুকোর মাকে সবকেকয় পেন্দিীয় হে 'আবেুল্লাহ্‌ও 'আবেুর রাহমাি’। [মুসর্েম]
Table 1: Components of the Classical Pathway.
Native component
C1(q,r,s)
C2
C3
C4
Active component(s)
C1q
C1r
C1s
C2a
C2b
C3a
C3b
C4a
C4b
Function(s)
Binds to antibody that has bound antigen, activates C1r.
Cleaves C1s to activate protease function.
Cleaves C2 and C4.
Unknown.
Active enzyme of classical pathway; cleaves C3 and C5.
Mediates inflammation; anaphylatoxin.
Binds C5 for cleavage by C2b.
Binds cell surfaces for opsonization and activation of alternate
pathway.
Mediates inflammation.
Binds C2 for cleavage by C1s. Binds cell surfaces for opsonization.
Table 2: Components of the Membrane-Attack Complex. (Classic Pathway)
Native component
C5
C6
C7
C8
C9
Active component(s)
C5a
C5b
C6
C7
C8
C9n
Function(s)
Mediates inflammation; anaphylatoxin, chemotaxin.
Initiates assembly of the membrane-attack complex (MAC).
Binds C5b, forms acceptor for C7.
Binds C5b6, inserts into membrane, forms acceptor for C8.
Binds C5b67, initiates C9 Polymerization.
Polymerizes around C5b678 to form channel that causes cell lysis.
Table 3: Components of the Alternate Pathway.
Native component
Active component(s)
C3
C3a
C3b
Factor B
B
Ba
Bb
Factor D
D
Properdin
P
Clinical Aspects of Complement:
Function(s)
Mediates inflammation; anaphylatoxin.
Binds cell surfaces for opsonization and activation
of alternate pathway.
Binds membrane bound C3b. Cleaved by Factor D.
Unknown.
Cleaved form stabilized by P produces C3
convertase.
Cleaves Factor B when bound to C3b.
Binds and stabilizes membrane bound C3bBb.
1. Deficiency of C5-C8 & Mannan-binding lectin
 Predispose to severe Neisseria bacteremia.
2. Deficiency of C3
 Severe, recurrent pyogenic sinus & resp. tract infections.
Department of Pharmacy
Immunology
Page 7 | 8
আবু হুরায়রা (রাাঃ) থেকে বর্ণত
ি র্তর্ি বকেি, রাসূেুল্লাহ্‌সাল্লাল্লাহু আোইর্হ ওয়া সাল্লাম বকেকেি:ِ“রমযাকির পর সবকেকয় উত্তম থরাযা হকে- আল্লাহর
মাস ‘মুহররম’ এর থরাযা।” (সর্হহ মুসর্েম: ১৯৮২)
3. Deficiency of C1 esterase inhibitor
 Angioedema → inc. capillary permeability and edema.
4. Deficiency of DAF
 Increased complement-mediated hemolysis → paroxysmal nocturnal hemoglobinuria.
5. Transfusion mismatches
 Activation of complement → generate large amounts of anaphylatoxins & MAC → red cell hemolysis.
6. Autoimmune diseases
 Immune complexes bind complement → low complement levels + activate inflammation → tissue damage.
7. Severe liver disease
 Deficient complement proteins → predispose to infection with pyogenic bacteria.
8. Factor I deficiency
 Low levels of C3 in plasma due to unregulated activation of alternative pathway → recurrent bacterial infections
in children.
 Mutations in factor I gene → implicated in development of Hemolytic Uremic Syndrome.
আনাস (িার িঃ) হতর্ বরণর্ত আতে। রর্রন বতলন, আরি িাসূলল্ল
ু াহ (সাল্লাল্লাহু আলাইরহ ওয়াসাল্লাি ) কে বলতর্ শুতনরেিঃ আল্লাহ র্া'আলা বতলন, কহ আদি সন্তান! র্ক্ষণ
র্ু রি আিাি োতে দু'আ েিতর্ থােতব এবং আিাি োতে প্রর্যাশা েিতব র্র্ক্ষণ আরি কর্ািাি গুনাহ িাফ েিতর্ থােব, র্া কর্ািাি গুনাতহি পরিিাণ র্ কবরশ র্
বড়ই কহাে । এ বযাপাতি আরি কোন কর্ায়াক্কা েিতবা না । কহ আদি সন্তান! কর্ািাি ক ানাতহি পরিিাণ রদ আোশ প ন্ত
ত কপাোঁতে ায় এবং র্ু রি রদ আিাি োতে িাফ
চাও, র্াহতল আরি কর্ািাতে িাফ েতি কদব। এ বযাপাতি আরি কোন পতিায়াই েিতবা না । কহ আদি সন্তান! রদ র্ু রি আিাি োতে পৃরথবীি সিান ক ানাহসহ হার ি হও
এবং আিাি সাতথ োউতে শিীে না েতি থাতো, র্াহতল আরিও ঠিে পৃরথবীি সিান ক্ষিা রনতয় কর্ািাি োতে এর তয় াতবা । সহীহ আর্-রর্িিীর িঃ র্াহেীে - আলবানী
(হািঃ ২৮০৫/ ৩৫৪০)
দৃঢ় িুরিন দুবলত িুরিতনি কচতয় কেয় এবং আল্লাহি রনেট অরিে রপ্রয় র্তব উভতয়ি িাতেই েলযাণ িতয়তে। কস রবষয় অর্ততন সদ্ধিয় হও া কর্ািাতে উপেৃর্ েতি এবং
আল্লাহি সাহা য চাও, আি আলসয েতিা না। রেন্তু রদ কোন রেেু [রবপদ বা অনাোঙ্ক্ষির্ পরিণরর্] ঘতট ায়, র্তব বতলা না ক
রদ আরি এিনঠট েির্াি র্তব এিনঠট
হর্, বিং বলিঃ এটা আল্লাহি রনিারির্
ত
র্ােদীি এবং রর্রন া ইচ্ছা র্া-ই েতিতেন। কেননা রনশ্চয়ই " রদ" শয়র্াতনি েিোতেি
ত
দুয়াি খুতল কদয়। (বুখািী, িুসরলি)
িুসলিান িুসলিাতনি ভাই। কস র্াি উপি র্ুলুি েিতব না এবং র্াতে র্ারলতিি হাতর্ কসাপদত েিতব না। ক কেউ র্াি ভাইতয়ি অভাব পূিণ েিতব, আল্লাহ র্াি অভাব
পূিণ েিতবন। ক বযদ্ধি (পৃরথবীতর্) কোন িুসলিাতনি রবপদ দূি েিতব, আল্লাহর্ায়ালা রেয়ািতর্ি রদন র্াি রবপদসিূহ দূি েিতবন। ক বযদ্ধি কোন িুসলিাতনি কদাষ
ক াপন েিতব, আল্লাহর্ায়ালা রেয়ািতর্ি রদন র্াি কদাষ ক াপন েিতবন। ( সহীহ বুখািী -২২৮০)
র্ারবি (িািঃ) হতর্ বরণর্ত আতে, রর্রন বতলন, নবী (সাল্লাল্লাহু আলাইরহ ওয়াসাল্লাি) কে উহূতদি ুতিি রদন এে কলাে প্রশ্ন েিল, আপনাি রে িািণা রদ আরি রনহর্ হই
র্তব আরি কোথায় থােব। িাসূলুল্লাহ (সাল্লাল্লাহু আলাইরহ ওয়াসাল্লাি) বলতলনিঃ ''র্ান্নাতর্''। র্খন র্াি হাতর্ি কখর্ুিগুতলা কফতল রদতয় কস ি
ু েিল, অবতশতষ শহীদ
হতয় ক ল। (বুখািীিঃ ৪০৪৬, িুসরলিিঃ ১৮৯৯)
াি িতনাত া আরখিাতর্ি প্ররর্ রনবব্ধ, আল্লাহ র্াি অন্তিতে অভাবিুি েতি কদতবন এবং র্াি অন্ততি পরির্ৃরি ও র্ু ঠি পয়দা েতি রদতবন আি র্াি এতলাতিতলা
োর্গুতলাতে সুরবনযস্ত েতি কদতবন এবং দুরনয়া এোন্ত অনু র্ হতয় র্াি োতে িিা কদতব। আি াি িতনাত া দুরনয়াি রদতে রনবব্ধ, আল্লাহ র্াতে সবদা
ত অপতিি
িুখাতপক্ষী িাখতবন আি র্াি ক াোতনা োর্গুতলাতেও এতলাতিতলা েতি কদতবন আি দুরনয়াি র্র্টু েুই কস লাভ েিতব া র্াি র্নয পূবরনি
ত ারির্
ত
রেল। আর্-রর্িরি ী
আনাস িারদয়াল্লাহু আনহু কথতে হাদীসঠট বণনা
ত েতিতেন।
PDF Link
https://drive.google.co
m/open?id=1KRzsNSuf
2d30wh1xpav32aB56cc
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Edited by
Syed Salauddin Parvez
PHA-16033
ssparvez16033@gmail.com
Edited by: Syed Salauddin Parvez, Third batch, Department of Pharmacy, MBSTU.
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