hypersensetivity

·         It is an exaggerated response of immune system that leads to the damage of the tissue and cells, and is shown by an individual on a second contact with the antigen.

·         Coombs and Gell classified the hypersensitivity reactions in four classes of reactions

Type I hypersensitivity:

·         The type I hypersensitivity is also known as allergic reaction. It is induced by antigens which are referred to as allergens.

·         Allergens are specifically non parasitic antigens capable of stimulating type I hypersensitivity responses.

·         The type I hypersensitivity reactions are IgE mediated reactions.

·         The reaction is stimulated by IgE to high affinity IgE-specific Fc receptors expressed on the mast cells and the basophil cells

·         When activated by the antigens (allergens) the IgE antibodies stimulates the mast cells and basophil cells to release primary mediators: vasoactive amines, stored in the granules (degranulation)

·         The chief mediators are the proteases, heparin and histamines etc..

·         The mediators are responsible for all the normal consequences of an acute inflammatory reaction. I.e. granulocyte chemotaxis, vascular permeability and all sorts of the consequences of inflammations.

·         The type I hypersensitivity is further classified as :

Ø  Anaphylaxis: this type of the type I hypersensitivity is highly rapid, life threatening, severe and are spread to whole body, they are caused due to the re-exposure of the individual to the antigen (allergens)

Ø  Atopy: if the tendency to develop allergic reactions is inherited genetically, they are called the atopic hypersensitivity reactions.

Type II hypersensitivity:

·         The type II hypersensitivity reactions cause the destruction of the host cells and tissues; by lysis or toxic mediators, hence they are also called as cytotoxic or cytolytic reactions.

·         It is an IgM and IgG mediated response.

·         It is caused by the binding of the antibodies to the cell or tissue antigens.

·         They (IgG and IgM) cause cell destruction by Fc-mediated mechanisms, either directly or indirectly activating the complement via the classical pathway.

·         Example of the hypersensitivity class ii reaction is the hypersensitivity shown by an individual who has been transfused blood of blood group other than that of the individual.

·         The antibodies attach to the cell membrane component, leading to complement fixation; this activates the complement chain and leads to either lysis or oposonization of the cell.

·         Lysis of target cell is analogous to that of cytotoxic T cells and involves the release of cytoplasmic granules, containing perforin and granzymes that activates the event leading to the apoptosis.

Type III hypersensitivity:

·         It is mediated by immune complexes of IgG antibodies with soluble antigens.

·         The circulating immunity complexes may accumulate at various tissue sites, where they activate complement and subsequently cause tissue cell lysis.

·         Normally these complements are phagocytized by the monocyte-macrophage system.

Type IV hypersensitivity:

·         Commonly it is known as delayed type of hypersensitivity.

·         Only class of hypersensitivity that is triggered by antigen-specific T cells. (cell mediated immunity reactions)

·         This is mediated by T-cell dependent effector mechanisms involving T_H cells.

·         This reaction has nothing to do with the antibodies.

Innate immunity: elements of innate immune system

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1. Innate immunity is present from birth.
2. It provides the first line of defense against pathogens
3. It is not specific to any one pathogen, but rather acts against all foreign molecules.
4. It also does not rely to previous exposure to the pathogens.
5. Its response is functional since birth and has no memory.
Elements of innate immunity:
1. Physical barriers:
Physical barriers are the first line of defence against microorganisms. It includes:

• Mucous membranes
• The acidic pH of sweat and sebaceous glands; fatty acids and hydrolytic enzymes inhibit the growth of microorganisms.
• The respiratory tract is lined by cilia (hair like projection) of epithelial membranes; the synchronous movement of cilia propels mucus entrapped microorganisms from these tracts.
• Conjunctiva is also specialized, the tears contains lysozyme, lactoferin, IgA and thus provide chemical as well as physical protection

In spite of these barriers, some microorganisms are able to penetrate the physical barriers. Then it is up to the adaptive and innate immune system to recognize and destroy them, without harming the host.

2. Chemical mediator:
a. Complement: it is a heat labile component of blood plasma that augments phagocytosis. This activity was said to complement the antibacterial activity of the antibody/
It also bridges the innate and adaptive immunity. The complement system is composed of over 30 serum proteins. Activation of complement in response to certain micro-organism results a controlled cascade of enzymatic reactions which targets the membranes of pathogenic organisms and lead to their destruction. A variety of specific and non-specific immunologic mechanisms can convert the inactive form of complement proteins to active forms with the ability to damage the membranes of pathogenic organisms, either destroying the pathogens or facilitating their clearance. Reactions between the complement molecules or fragments of complement molecules and cellular receptor triggers the activation of innate or adaptive immune systems.
b. Cytokines: the term cytokine is a generic term for any low molecular weight soluble protein or glycoprotein released by one cell population which acts as intercellular mediator. Interferon is cytokines made by cell in response to viral infection which essentially induce generalized antiviral state in surrounding cells.
c. Pattern recognition molecule: many molecules involved in innate immunity have the ability to recognize a give class on molecule. I.e. recognize pattern. Pattern recognition molecule that recognizes pattern associated molecular pattern (PAMP) may be soluble circular proteins or cell surface receptors. E.g. Manose-binding lectin (MBL) and C - reactive protein (CRP) are soluble pattern recognition molecules that bind to microbial surface and promote their opsonization.
3. Cellular defence: leukocytes are responsible for both specific and nonspecific immunity. Many specialized cell such as neutrophils, macrophages, monocytes, NK cells, participate in innate host defense mechanism. Once the pathogen invades the physical and chemical barriers, the specialized cells play and important role in protection, phagocytosis is fundamental protective. The phagocytosis is enhanced by the opsonization of pathogens. (opsonization: the process by which particulate antigen are rendered more susceptible to phagocytosis is called opsonization)
After ingestion the foreign particle is trapped in the phagosome (phagocytic vacuole), which fused with lysosome forming phagolysosomes. Now the antimicrobial and cytotoxic substances present within lysosome destroys the phagocytized micro-organism. The destruction of phagocytized micro-organism takes place as follows.
i. Oxygen dependent killing: during this process the phagocytes increase their O­₂ consumption (such as hydroxyl radicals, superoxide anions, hydrogen peroxide) which acts as antimicrobials.
ii. Oxygen independent killing: activated macrophages also synthesize lysozyme, defensin and various hydrolytic enzymes, who act without oxygen requirement
4. Inflammatory barriers:

•   Inflammation is an important non-specific dense reaction to cell injury.
•   The signs of inflammation are pain redness (erythema) swelling (edema) and heat.
•   Pain is caused due to increased vascular diameter which leads to increased blood flow, thus causing heat and redness in the area.
•   These blood vessels become permeable to fluid and proteins, leading to local swelling and an accumulation of blood proteins that aid in defence.
•   The inflammatory responses are mediated by a variety of signaling molecules. Activated macrophages produce chemo attractants (known as chemokine).
•   Some chemokine attract neutrophils, (which are the first cells, which are recruited in large numbers to the site of infection).
•   Other chemokine attract the monocytes and dendritic cells. The dendritic cells pick up antigens from the invading pathogens and carry them to nearby lymph nodes, where they present antigens to lymphocytes to marshal the forces of adaptive immune system.
•   Two principal mediators of inflammatory response are histamine (released by a variety of cells in response to injury of tissues), kinines (present in blood plasma in active form)

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Basic structure of antibodies

1. The antibodies reside in the serum.

2. The early experiments of kabat and Tiselius resolved serum proteins into three major non-albumin peaks i.e. α, β, ϒ

3. Antibodies are heterodimers. They have common structure of four peptide chains.

4. The structure consists of two identical light (L) chains and two identical heavy (H) chains.

5. Molecular weight of heavy chain (H) is about 50,000.

6. The molecular weight of the light chain (L) is about 25,000.

7. H and L chains are also called immunoglobulin.

8. Each light chain is bounded to heavy chain by disulphide bonds, and other non-covalent interactions such as salt linkage, hydrogen bond etc….

9. It is sometimes called as the dimers of dimer.

10. Around first 110 (or so) AA of amino-terminal region of light or heavy chain varies greatly among antibodies of different specificity, these segments of highly variable regions are called V-regions. i.e. V_L in light chain and V_H in heavy chain.

11. The V-region has an area called complementary-determining region called as CDRs. It is this CDR (on both light and heavy chain) that constitute the antigen binding site of antigen molecule.

12. The region of relatively constant region beyond the variable region have been dubbed C regions. I.e. C_L in light chain and C_H on heavy chains, the site for attatchment of the carbohydrates are restricted to the constant region.

Heavy chain sequencing revealed five basic varieties of heavy chain

a. The sequencing of revealed that the sequence of the heavy chain are very similar to the light chain.

b. The amino terminal part constitute of 100 to 110 amino acid shows great variation among myeloma heavy chains, so were named as V- chains.

c. The remaining part of chains revealed 5 basic sequence patterns corresponding to 5 diferent heavy chain constant regions (i.e. µ, δ, γ, ε, α)

d. Each of these five different heavy chains are called an isotype.

e. The length of constant region is , approximately 330 AA in δ, ϒ, α. And approximately 440 AA in µ, ε.

f. The class of antibody is determined by the type of heavy chain present.

ANTIBODY CLASS	AA length	TYPE OF HEAVY CHAIN
IgM	440	µ
IgE	440	ε
IgG	330	ϒ
IgA	330	α
IgD	330	δ

g. A single antibody molecule may have any one type of light chain, i.e. either kappa (Κ) or lambda(λ) light chain.

h. A single antibody molecule has identical pairs of heavy and light chain respectively. i.e. H₂L₂

i. The isotypes were further classified as subisotypes (similarly were the antibodies classified).

j. In humans there are following subisotypes.

1. α à α_1, α₂ (IgA₁, IgA₂)

2. ϒàϒ₁, ϒ₂, ϒ₃, ϒ₄ (IgG₁, IgG₂, IgG₃, IgG₄)

3. The δ, ε, µ has no subisotypes.

CLASS	H-CHAIN	SUBCLASS	LIGHT CHAIN
IgM	µ	none	K or λ
IgE	ε	none	K or λ
IgG	ϒ	ϒ1, ϒ2, ϒ3, ϒ4	K or λ
IgA	α	α1, α2	K or λ
IgD	δ	none	K or λ