Working of Immune System

Yahyea Baktiar Laskar
ZOODSC-501: Immunology (U4)
WORKING OF THE IMMUNE SYSTEM
Assistant Professor
Department of Zoology
Ramanuj Gupta Degree College
yahyea92@gmail.com
yahyeabaktiar.laskar@aus.ac.in

Structure and functions of MHC
• Major histocompatibility complex (MHC) is the cluster of gene arranged within a long
continuous stretch of DNA on chromosome number 6 in Human which encodes MHC
molecules.
• MHC molecule is a cell surface glycoprotein receptor present in APCs and acts as antigen
presenting structure.
• It plays vital role in immune recognition, including interaction between T cells and other
cell types.
• In Human MHC is known as Human Leucocyte antigen (HLA) complex.
• The genes of MHC are recognized in three classes, consequently there are three types of
MHC molecules: Class I, II and III MHC.
MHC is set of surface proteins located in the cell membrane of nucleated cells and play
major role in identifying self and non-self antigens.
Peter Alfred Gorer
(1907-1961)

MHC Class I
• Class-I MHC gene encodes glycoprotein molecule which expressed on the surface of all nucleated cells, except neurons
and platelets.
• MHC-I molecule contains a 45KDa α-chain associated non-covalently with a 12KDa β2 microglobulin molecule.
• Association of α-chain and β2 microglobulin is required for expression of class-I MHC molecule on cell membrane.
• Major function of MHC-I is to bind peptide antigens and present to CD8+ T cells (T-helper cells)
• The α-chain is a transmembrane glycoprotein.
• Anchored in the plasma membrane by its hydrophobic trans-membrane segment.
• Hydrophilic cytoplasmic tail.
• α-chain is made up of 3 domains (α1,α2 and α3). Each domain containing approximately 90 aa.
• α1 and α2 domains interacts to form a deep groove on the top which is a peptide binding cleft. It can binds antigen of
8-10 animo acids long.
• β2 microglobulin is a protein encoded by a highly conserved gene located on different chromosome.

MHC Class II
• Class-II MHC is the glycoprotein molecule expressed primarily on antigen presenting cells such as macrophages,
dendritic cells and B-cells.
• Contains two different polypeptide chains, 1 33 KDa α-chain and 28KDa β-chain which are associated by non-covalent
interactions.
• α-chain and β-chain of MHC-II is a membrane bound glycoprotein that contains external domains, a transmembrane
segment and a cytoplasmic tail.
• The cleft can bind antigenic peptide of 13-18 amino acids long.
• Major function of MHC-II is to bind peptide antigen and present to CD4 T cells.
• Activates B cells for antibody production.
• MHC-II plays a significant role in graft versus host response.
MHC Class III
• Class III MHC genes encode for various secreted proteins that have immune functions, including the component of the
complement system and molecules that are involved in inflammation such as cytokines.

Antigen Processing and Presentation
Cytosolic & endocytic pathway:
• The recognition of protein antigens by T-lymphocytes required that the antigens be processed by Antigen-presenting
Cells, then displayed within the cleft of the MHC molecules on the membrane of the cell.
• This involves the degradation of the protein antigens into peptides, a process known as antigen processing.
• When the antigen has been processed and degraded into peptides, it then associates with MHC molecules within the
cell cytoplasm forming a peptide-MHC complex. This complex is then transported to the membrane, where it is
displayed by a process of antigen presentation.
• The Class I MHC molecules bind peptides derived from endogenous antigens that have been processed within the
cytoplasm of the cell such as tumor proteins, bacterial proteins, or viral proteins, or cellular proteins, and processed
within the cytosolic pathway.
• Class II MHC molecules bind peptides derived from exogenous antigens that are internalized by phagocytosis or
endocytosis and processed within the endocytic pathway.

Cytosolic pathway:
• Processes and presents the endogenous antigen using the Class I MHC molecules.
• These proteins targeted for proteolysis have a small protein known as ubiquitin attached
to them.
• The ubiquitin-protein conjugate then gets degraded by a multifunctional protease
complex known as a proteasome.
• The peptides are then transported from the cytosol to the rough endoplasmic reticulum.
• This is enabled by the transporter protein, designated TAP (transporter associated with
antigen processing) is a membrane-spanning heterodimer consisting of two proteins:
TAP1 and TAP2.
• Additionally, TAP proteins favor peptides with hydrophobic or basic carboxyl-terminal
amino acids, which is the preferred anchor residue for class I MHC molecule.
• After binding, the class I molecule displays increased stability, exit from the RER, and
proceed to the cell surface via the Golgi.

Endocytic pathway:
• Antigen-presenting cells can internalize antigen by phagocytosis, endocytosis, or both.
• When the exogenous antigen is internalized, it is degraded into peptides in the
compartments of the endocytic processing pathway.
• It appear at the cell surface in the form of a peptide-class II MHC complex.
• Internalized antigen moves from the early to late endosomes and later to the lysosomes
where they encounter the hydrolytic enzyme.
• When the MHC II has been synthesized within the RER, three pairs of class II chains
associate with a preassembled trimer of a protein known as an invariant chain (CD74).
• The trimeric protein interacts with the peptide-binding cleft of the class II MHC
molecules, preventing any endogenously derived peptides from binding to the cleft while
the MHC class II remains within the RER.
• They exit from the RER, and routing it to the endocytic processing pathway from the
trans-Golgi network into the endocytic vesicles.

Clinical Significance of Antigen processing and presentation:
• Sometimes the antigen-presenting cells (APCs) can deliver self-antigens which cause autoimmune diseases. When the
self-antigens are presented to the T-cells, it initiates an immune reaction against our own tissues, causing autoimmune
disorders such as Graves Disease, rheumatoid arthritis.
• In Graves’ disease, TSHR (Thyroid-stimulating hormone receptors) acts as the self-antigen, which is presented to T-cells
activating B-cells which produce autoantibodies against TSHRs in the thyroid. This leads to the activation of TSHRs
causing hyperthyroidism and leading to goiter.
Further reading: https://microbenotes.com/mhc-antigen-processing-presentation/

Basic properties and functions of cytokines
Basic properties of cytokines:
• Cytokines are small immunomodulating proteins that range from 5-25 kDa.
• Cytokines may act on the cell that produces them (autocrine action), on the nearby cells (paracrine action) or on
distant cells (endocrine action).
• They are pleiotropic in nature.
• Cytokines can work both antagonistically and synergistically.
• Cytokines are produced by various cells such as macrophages, mast cells, B-lymphocytes, T-lymphocytes, fibroblasts as
well as endothelial cells, among others.
• The cytokines produced by lymphocytes are lymphokines, monocytes are monokines, chemotactic activities are
chemokines, and leukocytes are interleukin.
The functional classification of the cytokines:
• Type 1 includes TNFα, IFN-γ, etc., which enhance cellular immune responses.
• Type 2 includes IL-4, IL-10, TGF-β, IL-13, etc., which enhance antibody responses.

Basic properties and functions of cytokines
Functions of cytokines:
• Cytokines are majorly produced by helper T cells and macrophages. During a
peripheral nerve injury, the employed macrophages, mast cells and
endothelial cells produce cytokine at the site of injury for nerve regeneration.
• Cytokines such as IL-6 and TNF-α are involved in the upregulation of
inflammatory reactions.
• IL-1β released by monocytes and macrophages are released at the time of
inflammation, injury, invasion and infection.
• The chemokines function for the activation and migration of leukocytes. They
are also released during demyelinating and neuroinflammatory diseases.
• Various cytokines are also involved in modulating the neuronal activity of the
neurons of the central and peripheral nervous systems.
Further reading: https://byjus.com/biology/cytokines/

Complement System
Complement System:
• Opsonization is an immune process which uses
opsonins to tag foreign pathogens for elimination
by phagocytes.
• The complement system is made up of a large
number of distinct plasma proteins that react
with one another to opsonize pathogens and
induce a series of inflammatory responses that
help to fight infection.
• Complement is a chain of enzymes whose
activation eventually results in the disruption of
cell membranes and the destruction of cells or
invading microorganisms.

Complement System
Functions of the Complement System:
• Lysis of foreign cells by antibody-dependent or antibody-independent pathways; opsonization or uptake of particulate
antigens, including bacteria, by phagocytes; activation of inflammatory responses; and clearance of circulating
immune complexes by cells in the liver and spleen.

Complement System
History of Complement System:
• The name “complement system” is derived from
experiments performed by Jules Bordet (1890).
• Fresh serum containing antibacterial antibody if
interacted with bacteria at 37°C, the bacteria were
lysed.
• If, however, the serum was heated to 56°C or more, it
lost its lytic capacity.
Conclusions:
• Serum must contain some heat-labile component that
assists or complements the lytic function of antibodies.
• This component was later given the name complement
by P. Ehrlich.

Complement System
Components of Complement System:
• Made up of a number of distinct serum (blood plasma) and membrane proteins.
• The proteins are synthesized primarily by liver hepatocytes, blood monocytes, and tissue macrophages, epithelial cells
of gastrointestinal and urinogenital tracts.
• The complement products amplify the initial antigen-antibody reaction and convert that reaction into a more effective
defense mechanism.
• Continuous proteolytic cleavage and activation of successive complement proteins lead to the covalent bonding or
fixing of complement fragments to the pathogen surface.
• The proteins that form the complement system are labelled numerically with the prefix C (e.g., C1 –C9).
• Some complement components are designated by letter symbols (e.g., factor B, D, P) or by trivial names (e.g.,
homologous factor).

Complement System
Components of Complement System:
• Each precursor of complement is cleaved into two major
fragments- named as larger fragment (designated as ‘b’) and
smaller fragment (designated as ‘a’).
• larger ‘b’ fragment has two biologically active sites—one binds to
cell membranes of the target cell towards the site of activation
and the other for enzymatic cleavage of the next complement
component.
• The smaller ‘a’ fragments diffuse from the site and play a role in
initiating a localized inflammatory response (chemotactic
activity).
• Each enzyme molecule activated at one step, can generate
multiple activated enzyme molecules at the next step (cascade
activity).

Complement System
Classical Pathway:
• Although the pathways of complement activation differ, all of
them result in the generation of enzyme complexes that are able
to cleave the most abundant complement protein, C3.
• Proteolysis of C3 and late steps, which lead to the formation of a
protein complex that lyses cells.
• Antigen complexed with IgM and IgG, can initiate the classical
pathway.
• Main components include C1, C2, C3 and C4.
• Formation of an antigen-antibody complex induces
conformational changes in the Fc portion of the IgM molecule that
expose a binding site for the C1.
• C1 has two substrates, C4 and C2.

Complement System
Classical Pathway:
• C4 is activated when C1 hydrolyzes it into small fragment (C4a)
and the larger fragment (C4b).
• C2 proenzyme attaches to the exposed binding site on C4b, where
the C2 is then cleaved by the neighboring C1; C2b diffuses away.
• The resulting C4b2a complex (C3 convertase).
• Hydrolysis of C3 by C3 convertase generates C3a and C3b.
• Some of the C3b binds to C4b2a to form a trimolecular complex
C4b2a3b, called C5 convertase.
• C3b binds C5, so that the C4b2a component can cleave C5 into
C5a and C5b.
• C5a diffuses away and C5b attaches to C6 and initiates formation
of the Membrane attack Complex (MAC).

Complement System
Alternative Pathway:
• It is dominant to the classical and lectin pathway during normal physiological
conditions.
• Does not require the formation of antigen-antibody complexes.
• This pathway is constantly activated at a low level, in which C3 gets hydrolyzed
to C3b, which directly to these surfaces of foreign antigens.
• The hydrolyzed protein then binds to serum factor B. This complex is cleaved
by serine protease Factor D, forming C3 convertase (C3b+Bb).
• This complex can now activate more C3 via a powerful amplification cycle.
• The convertase complex, in turn, cleaves C3 to C3a and C3b.
• When a second C3b adds to it, the C5 convertase is synthesized.
• C5 convertase cleaves C5 into subunits C5a and C5b. C5b recruits C6, C7, C8,
and C9 forming MAC that induces cell lysis.

Complement System
Lectin Pathway:
• Carbohydrate-binding proteins called lectins initiate the reaction after binding
to the surface of a wide range of pathogens.
• The recognition of mannose-containing sugars on pathogens by Mannose
Binding Lectin (MBL) initiates a reaction.
• MBL forms a complex with 2 protease zymogens MASP-1 and MASP-2,
homologous to C1r and C1s.
• Activated MASP-1 and MASP-2 cleave C4 and C2.
• C4 is cleaved into C4a and C4b. C4b attaches to the surface of the pathogens
inducing C2 to bind, which is cleaved by MASP2 to form C2b and C2a. C2a binds
to C4b, forming complex C3 convertase.
• The convertase complex, in turn, cleaves C3 to C3a and C3b.
• The membrane attack complex (MAC) is formed following the same pathway as
the classical pathway of the complement system.

Disclaimer: The information/images in this study material has been adapted from various sources including but not limited to books, journals, websites, and
related materials openly available in the internet. This will be purely utilized for academic purpose only, by college students. The author has no intension of
using these information/images/other materials that may be copyrighted and included in this study material for commercial benefit.

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