introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system, which is not adaptable and does not change over the course of an individual's lifetime.
consists of three pathways: 1. alternative
2. classical
3. lectin pathway
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
introduction of adaptive immunity. classification of adaptive immunity, factor affecting it and mechanism of adaptive immunity comparison between adaptive immunity and innate immunity. characteristic of adaptive immunity . cell mediated immune responses immunoglobulins
types of immunoglobulins. functions of immunoglobulins, hypersensitivity reactions
The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system, which is not adaptable and does not change over the course of an individual's lifetime.
consists of three pathways: 1. alternative
2. classical
3. lectin pathway
T-Cell Activation
• Concept of immune response
• T cell-mediated immune response
• B cell-mediated immune response
I. Concept of immune response
• A collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules in the immune system.
II. T cell-mediated immune response
• Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc.
This presentation is organized with the help of other presentations, text book of immunology and some internet resources for better understanding of students.
Complement System comprises of Complement proteins that function to augment the antibodies in killing bacteria by the formation of Membrane Attack Complex.
This ppt describes the different pathways of activation complement proteins and MAC formation.
Immunology is the study of the immune system and is a very important branch of the medical and biological sciences. The immune system protects us from infection through
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Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
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June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...
Complement & complement system
1. COMPLEMENT & COMPLEMENT SYSTEM
DEPARTMENT OF MICROBIOLOGY
GOVERNMENT COLLEGE UNIVERSITY FAISALABAD
Iqbal Danish & Summiya Akram
m.Phil 2nd semester
2. Complement:
The part of immune system consists of series of proteins circulating in blood or
body fluids.
It is named “complement system” because it was first identified as a heat-labile
component of serum that “complemented” i.e., augment / enhance the effects of
other components of immune system e.g. antibodies
in the killing of bacteria.
3. These proteins circulate in an inactive form but become sequentially activated in an
enzyme cascade when recognize molecular component of microorganisms.
Activation of complement:
Activated via three different pathways which can each cause the activation of C3
cleavage into:
Activated C3 triggers the lytic pathway.
C5a, produced by this process, attracts macrophages and neutrophils and also
activates mast cells
4. History:
Research on complement began in the 1890s.
when Jules Bordet at the Institute Pasteur in Paris showed that some cholera
vibrio are lysed by sheep anti cholera serum.
Heating the antiserum at 56℃ for 30 min destroyed its bacteriolytic activity.
The addition of fresh serum to the heated anti serum restored its lytic activity.
He concluded that bacteriolysis required two different substances:
• heat-stable specific antibodies that bound to the bacterial surface.
• heat-labile (sensitive) component responsible for the lytic activity.
The famous immunologist Paul Ehrlich, carried out similar experiments and
coined the term complement, defining it as
“the activity of blood serum that completes the action of antibody.”
5. Properties of Complement System:
• Present in sera of all mammals, animals, birds, amphibians and fish .
• Heat labile
• Constitutes 5% of normal serum protein .
• These proteins are not immunoglobulins and their concentrations in serum do not
increase after immunization.
• Activity of complement destroyed by heating sera to 56℃ for 30 minutes.
• IgM and IgG are the only immunoglobulin capable of activating complement
(classical pathway).
6. • Complement activation can be initiated by complex polysaccharides or enzymes
(alternative or properdin pathway).
• Primary role is cell lysis.
• Contribute to chemotaxis, opsonization, immune adherence, anaphylatoxin
formation, virus neutralization, and other physiologic functions.
• Binds only with antigen-antibody complex.
• Binds to Fc fragment on the immunoglobulin.
7. Components of Complement System:
Components are designated by numbers (e.g. ; C1 – C9) or letters (e.g. : Factor
D).
Synthesis of components:
• In liver by hepatocytes.
• Blood monocytes
• Tissue macrophages
• Fibroblasts
• Epithelial cells of the gastrointestinal and genitourinary tracts.
11. Proteins involved in complement system:
Exist as zymogens or proenzymes (inactive forms) in the circulation that must first
be cleaved or undergo conformational changes prior to activation.
Example: C4
← →
C4a C4b
a = smaller fragment b= larger fragment.
Diffusion & signaling remains bound to microbe
Exception: C2
C2a = large fragment
C2b = small fragment
13. Initiator Proteins:
These proteins initiate the complement pathway by binding to pathogens.
Undergo the conformational change for their biological activity.
Enzymatic Mediators:
Enzymatic mediators (e.g., C1r, C1s, MASP2, and factor B) activate other components of the
complement cascade, the C3 and C5 convertases, which cleave C3 and C5, releasing active
components that mediate all functions of complement.
Membrane-binding components or opsonin:
Upon activation of the complement cascade, several proteins are cleaved into two fragments,
each of which then takes on a particular role.
For C3 and C4, the larger fragments, C3b and C4b, serve as opsonin enhancing phagocytosis
by binding to microbial cells.
Inflammatory Mediators:
Some small complement fragments act as inflammatory mediators that enhance the blood
supply to the area in which they are released, by binding to receptors on endothelial cells.
14. Also attract other cells to the site of tissue damage. These fragments are called anaphylatoxins,
meaning substances that cause anaphylaxis (“against protection”).
E.g. C3a, C5a, and C4a.
Membrane Attack Proteins:
These proteins insert into the cell membranes of invading microorganisms and punch holes that
result in lysis of the pathogen.
E.g. C5b, C6, C7, C8, and multiple copies of C9.
Complement Receptor Proteins:
Receptor molecules on cell surfaces bind complement proteins and signal specific cell
functions.
E.g. some complement receptors such as CR1 bind to complement components such as C3b on
the surface of pathogens, triggering phagocytosis of the C3-bound pathogen.
Regulatory Proteins:
Limit the effects of complement by promoting their degradation or preventing their binding to
host cells.
15.
16. Regulation of complement system
C1 inhibitor
important regulator of classic pathway.
A serine protease inhibitor (serpin).
Irreversibly binds to and inactivate C1r and C1s, as well as MASP in lectin pathway.
Factor H
regulate alternative pathway.
Reduce amount of C5 convertase available.
With both cofactor activity for the factor I-mediated C3b cleavage, and decay accelerating
activity against C3bBb (C3 convertase).
Properdine
Protects C3b and stabilize C3 convertase.
17. Factor I
Cleave cell-bound or fluid phase C3b and C4b
Inactivates C3b and C4b.
Decay accelerating factor (DAF)
Glycoprotein on surface of human cells.
Prevents assembly of C3bBb or accelerates disassembly of performed convertase there is
no formation of MAC.
Acts on both classical and alternative.
C4b-binding protein(C4BP)
Inhibits the action of C4b in classical pathway.
Splits C4 convertase and it is a cofactor for factor I.
18. Complement receptor 1(CR-1)
co-factor for factor I, together with CD46.
Protectin (CD590) and vitronectin (S protein)
Inhibits formation of MAC by binding C5b678.
Present on self cells to prevent complement from damaging them
19. Complement system and immunity:
Complement system and humoral immunity:
Complement is an important part of immune system.
Help in activation and proliferation of plasma cell which form antibodies.
Complement is part of innate immune response, but it also play its role in adaptive immunity.
The major functions of the complement system are opsonization, lysis, and generation of the
inflammatory response through soluble mediators.
Complement enhances B-cell immunity principally through CRs, CR1 (CD35) and CR2
(CD21), expressed on B lymphocytes and follicular dendritic cells (FDCs).
CR2 forms a receptor complex with the signaling protein CD19 and the Tetra span protein CD81
to form the B-cell co-receptor complex (CD21-CD19-CD81), which supports an enhanced signal
via the B-cell receptor (BCR; e.g., surface immunoglobulin).
When it encounters antigen coated with complement opsonin (e.g., C3d), resulting in the
reduction of B-cell activation threshold by several orders of magnitude.
20. In all these mechanism of B cells activation, complement play its role as an adjuvant to B
cells.
Receptors like CD21, CD19 and CD81 are also present on immature B cells when they
migrate from bone marrow and during positive selection.
Coupling C3d to low-affinity antigen, which (if uncoupled) would cause B-cell death,
results in not only survival but also B-cell activation and production of antibody,
suggesting a role of complement in the 'instruction' of naive B cells in the periphery.
Activation of mature peripheral and follicular B cells by complement-opsonized antigen
leads to their migration to the lymphoid T-cell: B-cell boundary, where helper T cells
provide co-stimulation via CD40, leading to B-cell activation and expansion.
Activated B cells initiate the formation of germinal centers (GCs), where CRs on B cells
enhance BCR signaling, leading to effective differentiation into plasma and memory B
cells
21. Complement role in CMI:
It was thought that complement only play its role in humoral immunity.
Later, it was observed in an experiment that priming of both CD4 and CD8 T cells was
reduced in C3-deficient mice during pulmonary influenza challenge, it suggested a more
generalized role of complement.
A potential role of complement in T-cell immune responses to viral and alloantigen has
now been demonstrated in a number of other studies.
C5aR has been shown to be essential for the modulating effect of complement on T-cell
immunity in various models.
Mice treated with C5aR antagonists produced fewer antigen-specific CD8 T cells,
following infection with influenza type A.
A lot of hypothesis suggest complement role in T cells mediated immunity.
But exact mechanism of complement role yet to be discovered and work is being done.
22. Stages of complement activation and complement
pathways:
Three main stages in the activation of complement by any pathway are
1. Formation of C3 convertase .
2. Formation of C5 convertase.
3. Formation of membrane attack complex.
23. Classical Pathway:
Immune complex is necessary when
antigen enter the body antibody binds
to it inducing changes in Fc portion
of antibody that provide binding site
for C1 protein.
Immune complex bound to C1 calls
protein C4 which is cleaved into C4a
and C4b. C4b attaches target surface
near C1q.
C4b attracts C2. C2a binds C4b
forming the C4b2a complex known
as C3 convertase.
C3 convertase cleaves large number of
C3 molecule. C3b binds to microbial
surface or to the convertase itself.
24. C3b with C3 convertase forms C5 convertase that activate C5.C5b stabilize by
binding C6 than this complex binds to C7.C5bC6C7 complex is inserted into
phospholipid by layer of cell membrane which further bind to C8 .
C5b678 activate C9 to form a macromolecule structure called the membrane
attack complex.
MAC makes whole in the bacterium, intracellular contents leak out.
cell can not maintain its osmotic stability and lyses occur by an influx of water
and loss of electrolytes.
25.
26. Alternative Pathway:
Antibody independent pathway.
Many cell surface substances like lipopolysaccharide, fungal cell wall and viral
envelope can initiate the process by binding C3 and factor B
Complex cleavage by protease, factor D to produce C3bBb (act as C3 convertase
to form C3b).C3b bind to the surface and than point to the factor B.
C3 convertase forms C5 convertase which ultimately forms a membrane attack
complex as in classical pathway.
27.
28. Lectin pathway(Mannose binding lectin
pathway):
MBL pathway is activated when
circulating lectin binds to mannose
residues on glycoprotein or
carbohydrates e.g. Salmonella, listeria,
Neisseria.
MBL is protein increase during
inflammation lectin recognize and bind
carbohydrate for complement
activation.
MBL-associated serene protein form
tetrameric complex that similar to C1r
and C1S.it cleaves C4 and C2 forming
C3 convertase that form C5
convertase.
31. Role of Complement in Diseases:
Complement system plays a critical role in inflammation and defense against some
bacterial infections.
Mast cells are widely distributed in the connective tissue around blood vessels and
Are among the first responders during inflammation.
Complement may also be activated during reactions against:
Incompatible blood transfusions, and
During the damaging immune responses that accompany autoimmune disease.
32. Complement Deficiency:
Complement deficiency is an immunodeficiency of absent or suboptimal functioning of one or
more of the complement proteins.
Many complement disorders are never diagnosed because of the redundancies in the
immune system. Some studies estimated that less than 10% are identified.
Complement deficiencies are said to comprise between 1 and 10% of all primary
immunodeficiencies.
Hypocomplementemia may be used more generally to refer to decreased complement levels.
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 susceptibility to
meningococcal disease.
33. Deficiencies can be:
Acquired
Inherited
Results in weaker immune response to infections.
These deficiencies can cause:
Contraction of smooth muscles.
Bronchial constrictions.
Increased vascular permeability.
34. Deficiency in C1, C2, C3, C4:
Remove Ag-Ab complex
Lack in these proteins cause:
Lupus like illness.
Chronic renal disease.
Deficiency in C5, C6, C7, C8:
Repeated Neisseria infections.
Risk of gonorrhea & meningitis.
Deficiency in C9:
Cause no problems.
35. Proteins in Defects Functions Influenced Diseases
Deficiency of C3- Inability of cleanup of IC
complement activation
Severe recurrent pyogenic &
respiratory tract infections
C1INH Loss of control in the
production of inflammatory
mediators
Angioedema or HANE
DAF, 59 Cytotoxic function of
complement to host cell
Paroxysmal nocturnal
hemoglobinuria (PNH)
Mismatched ABO transfusion Hemolysis, shock
Deficiency of C5-C8 & MBL Enhances susceptibility to
Neisseria infections
Deficiency of C1, C2, C4 Deficiency in the activation of
classical pathway
SLE, pyogenic infections
Factor H Loss of control in the
activation of alternative
pathway,
Low concentration of C3 in the
serum
SLE, pyogenic,
Glomerulonephritis
36. Immune Effects of Complement Products:
Opsonization
Chemotaxis
Triggers inflammation
Cytolysis
Activation of B lymphocytes
Anaphylatoxins
Removing harmful immune complexes from the body
37. Opsonization:
Promoting the attachment of antigens to phagocytes.
C3b & C1q; enhance phagocytosis.
Chemotaxis:
C5a also act as a chemo attractant for phagocytes.
C5a and C5,6,7 complex → attract neutrophils.
C5a – enhance adhesiveness of neutrophils to the endothelium.
Triggering Inflammation:
C5a is the most potent complement protein triggering inflammation.
38. Cytolysis:
Disrupt the membrane & the entry of water and electrolytes into the
cell.
C5b6789n, functions as a Membrane Attack Complex (MAC)
Activation of B lymphocytes:
Serving as a second signal for activating naive B lymphocytes.
Anaphylatoxins: (fragments C3a, C4a & C5a)
Cause degranulation of mast cells that releases histamine and other
vasoactive substances that increase vascular permeability.
Bind directly to smooth muscles of bronchioles - bronchospasm
39. Diagnostic Tools:
Among the diagnostic tests that can be done in determining if an
individual has complement deficiencies is:
Blood analysis by testing overall complement activity
• By detecting CH50 or CH100.
Immunochemical methods/test.
C3 deficiency screening.
Test for specific protein levels e.g. C3 or C4
40. Treatment:
No specific treatment is available for complement deficiencies.
However depend on the type of case:
• In case of overactive immune response give immunosuppressors.
• In case of underactive immune response give prophylactic antibiotics.
Acute attacks of (HAE), C1INH deficiency, have been successfully treated with
infusion of vapor-heated C1 esterase inhibitor.
These treatments are recommended only in adults.
A study in the Netherlands indicated efficacy of self-administration of plasma-
derived C1INH concentrate for prevention and treatment of angioedema attacks
in patients with C1INH deficiency.