Adaptive & Innate Immunity

The Immune Response and Immunity Immune response ▫ Innate (non-specific) ▫ Adaptive (specific):  Primary: when encountering the microorganism for the first time.  Secondary: in recurrent infections (memory)

Acquisition of Immunity ▫ Natural: - active - passive ▫ Artificial: - active - passive

Naturally Acquired Immunity Active: ▫ Acquired through contact with microorganisms (infection). ▫ Provides long term protection. Passive: ▫ Antibodies pass from mother to fetus across placenta or in breast milk (IgG) ▫ Provides immediate short term protection (few months)

Artificially Acquired Immunity Active: ▫ Antigens introduced through vaccination. ▫ Provides long term protection. Passive: ▫ Induced by the transfer of antibodies. ▫ Referred to as: Immune serum. globulins(ISG), immune globulins (IG) or gamma globulins ▫ Provides immediate short term protection

immunity adaptive natural active passive artificial active passive innate

Soluble mediators of the adaptive immune system:  Immunoglobulins.  Cytokines and interferons.  Complement.

Immunoglobulins Immunoglobulins (Ig): Are gamma globulins (proteins) of defined specificity for different epitopes that make up antigens. They are produced by plasma cells (differentiated B cells).

N epitopes

Immunoglobulins are divided into five classes (isotypes): Three major classes ( IgG, IgM, IgA). Two minor classes (IgD and IgE).

N Basic Structure of Immunoglobulin: The immunoglobulin molecule consists of four polypeptides chains: two heavy (H) and two light (L) chains fastened together by disulfide bonds.

Heavy and light chains consist of two different domains (constant, and variable). A light chain variable domain and a heavy chain variable domain together form a pocket that constitutes the antigen-binding region (Fab). The flexibility of Ig is associated with the presence of the hinge region.

Heavy chains are designated by using of Greek letters ( α, γ, δ, Є, and μ), and the immunoglobulins produced are IgA, IgG, IgD, IgE, and IgM, respectively. Each immunoglobulin isotype carry one type of light chain kappa(κ) or lambda(λ) chains.

Immunoglobulins Isotypes: IgG IgG accounts for approximately % of the total serum Ig It is the most abundant antibody produced during secondary humoral immune response. Have monovalent affinity. It is the only class that can cross the placenta.

IgG structure: n

IgM: Form ~ 5-8 % of serum immunoglobulins. Present on B lymphocyte surfaces. Normally secreted as a J-chain containing pentamer. (either as a B cell bound monomer or as a secreted pentamer). Dominates in early primary immune response. Anti-A and Anti-B blood groups. Complement fixation. Multivalent avidity (10 antigens).

IgM Structure: n

IgA:  It accounts for 10-16% of serum Igs.  Abundant in saliva, tears, intestinal mucus, bronchial secretions, milk, prostatic fluid (body fluids & secretions, secretory IgA).  The predominant Immunoglobulin produced in Peyer’s patches (illume submucosa), tonsils and other submucosal lymphoid tissue.  It has two subclass: in - Monomer in the serum. - Dimer when secreted (secretory IgA).  IgA1: IgA2 ratio in blood is 5:1

IgD Has a molecular weight of 180 KD. Present as monomer on B-cell surface.

IgE:  Form less than 1% of total serum Igs.  A unique high affinity Fc receptor on mast cell and basophils. (bounded)  Great role in allergy, through cross linking and release of histamine from mast cells and basophils.  Play a role in helminths infection.

Summary There are 5 isotypes of immunoglobulins. IgG is the most abundant in serum, the most important in secondary infections and the only one that can cross the placenta. IgM is the most important in the primary exposure and in complement fixation.

The secretory IgA is most important in immunity in body secretions, submucosa and lumens. IgD is bounded to the surface of B cells. IgE is bounded to the mast cells and basophils and is the most important in allergic reactions and helminths infestation.

Second Lecture

Primary & Secondary Antibody Response Primary Response ▫ Following the first exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG Secondary Response ▫ Following exposure to previously encountered antigen, there is a rapid rise in IgG and slow or no rise in IgM

Molecules of Cellular Interaction:  Cytokines: low-molecular weight soluble protein messengers that are involved in: ▫ Cellular interaction; inflammatory response in innate and adaptive immunity. ▫ Cellular growth, differentiation, and repair mechanism.  Cytokines are produced by a wide variety of immune and non-immune somatic cells.  Cytokines produced by lymphocytes are known as lymphokines.

N N CytokineCellular Source TargetsFunction IL-1Macrophage, B cell T cell, B cell, Endothelial cells. Leukocyte activation, endothelial adhesion IL-2CD4 cell (TH 1 ) T cell, B cell, NK cell, macrophages T cell proliferation. IL-4, IL-5CD4 cell (TH 2 ) B cell, T cell, EosDifferentiation of TH 2 and B cell IL-10, IL-13TH 2, CD8 cellsB cell, TH 2, Macrophage. Inhibits IL-2, and INFγ. Down reg. IL-12 TNF-αMac, PMN, T, B cells. Mac, PMN, T, End. Inflammatory Mediator. TNF-βLymphocytesWide Variety of cells Inflammatory Mediator.

Cytokines and Immune cells interaction: N - Macrophages (phagocytosis) - CD8 T cytotoxic - Intracellular pathogens (cell mediated immunity) - B cell - Immunoglobulin - Extracellular pathogens (humoral mediated immunity; phagocytosis independent) IL-4, IL-10, IL-13

Interferons (IFNs): are low molecular weight soluble proteins. Activated by presence of intracellular pathogens such as viruses,bacteria, parasites or tumor cells. Released by lymphocytes and other somatic non-immune cells. Major action: - anti-viral infection. - Fight tumors.

N N InterferonsCellular SourceTargetsFunction INF-α Lymphocytes, Epithelium, DC fibroblasts. Wide variety of cells. -Up-regulates MHC Class I. -Inhibit viral proliferation INF-β Epithelium, fibroblasts. Wide variety of cells. Up-regulates MHC Class I. Inhibit viral proliferation INF-γ CD8*& CD4*T cells, and NK cells. T, B, macrophages, NK, endothelial cells. Anti-viral. Anti-parasitic. Enhances MHC Class I and II expression.

Complement system:  Complement system: series of soluble enzymes and proteins (C1,C2…….C9) + other actors that function in both innate and adaptive immune response against pathogens.  Complement activation can be initiated via: ▫ Classical pathway. ▫ Alternative pathway. ▫ Mannan lectin pathway.

Classical pathway of complement:  Starts by antigen - antibody interaction.  C1 (q, r, s) binding to the Ag- Ab complex.  C1qrs will split C2 and C4.  C4b2b will split C3. (C4b2b = C3 convertase).  C4b2b3b = C5 convertase.  C5b will adhere to the microbe.  continue tell MAC formation (C5, C6, C7, C8 and multiple C9).

Alternative pathway: Activation of the alternate pathway started from C3 in the presence of the microbe. C3 splits into C3a and C3b. C3b bind to the microbe surface with factor B.( C3bBb= C3 convertase) C3Bb3b = C5 convertase, this will split C5 and the process will continue tell formation of the membrane attack complex (MAC).

Mannan lectin pathway Mannan is polymer of the sugar mannose (part of the bacterial cell wall). Lectins are serum proteins that bind to mannan. This pathway is activated by binding of lectin to mannan on certain microbes, and continue tell MAC formation.

N

The Complement Anaphylatoxins: The small fragments (C3a, C4a, C5a) act as anaphylotoxins. They attract and activate neutrophils, phagocytes and mast cells to the site of infection. Produce an inflammatory reaction.

Mechanism of Inflammation: N