Describe the Various Classes of Immunoglobulins & its Functions

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Immunoglobulins: classes and functions

Immunoglobulins (Igs), also called antibodies, are glycoproteins produced by plasma cells. They bind specific antigens through their variable (Fab) regions. Their heavy-chain constant region determines the antibody class and its effector functions. The five major classes are IgG, IgA, IgM, IgD, and IgE. NCBI Immunobiology

General functions of antibodies

Antibodies protect against extracellular microbes and toxins by:

Neutralization: blocking attachment of microbes, viruses, or toxins to host cells.
Opsonization: coating microbes to make phagocytosis by neutrophils and macrophages easier.
Complement activation: promoting inflammation, opsonization, and lysis of susceptible microbes.
Agglutination: clumping particulate antigens such as bacteria.
Antibody-dependent cellular cytotoxicity (ADCC): enabling NK cells and other cells to kill antibody-coated targets.
Mucosal protection and allergic/anti-parasitic responses.

Class	Heavy chain	Main form/location	Main functions
IgG	γ (gamma)	Monomer; blood and extracellular fluid	Secondary response, neutralization, opsonization, complement activation, ADCC, passive fetal immunity
IgA	α (alpha)	Monomer in serum; dimer in secretions	Mucosal immunity and neutralization at body surfaces
IgM	μ (mu)	Pentamer in serum; monomer on B cells	First antibody in primary response; strongest complement activation and agglutination
IgD	δ (delta)	Mainly B-cell surface	B-cell antigen receptor and regulation of B-cell activation
IgE	ε (epsilon)	Bound to mast cells and basophils	Immediate allergy, anaphylaxis, and defense against helminths

1. Immunoglobulin G (IgG)

Most abundant immunoglobulin in serum, about 75% of serum immunoglobulins.
Exists as a monomer.
Has four subclasses: IgG1, IgG2, IgG3, and IgG4.
Predominates in the secondary or memory immune response.
Functions:
- Neutralizes toxins, viruses, and microbes.
- Opsonizes bacteria, facilitating phagocytosis through Fc receptors on macrophages and neutrophils.
- Activates the classical complement pathway, especially IgG1 and IgG3.
- Mediates ADCC by allowing NK cells to recognize antibody-coated target cells.
- It is the only immunoglobulin that crosses the placenta, providing passive protection to the fetus and newborn.

Sources: Cummings Otolaryngology Head and Neck Surgery, p. 2645; Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 1359-1360.

2. Immunoglobulin A (IgA)

Main immunoglobulin of mucosal surfaces and secretions.
Present in tears, saliva, nasal and bronchial secretions, gastrointestinal fluid, genital secretions, colostrum, and breast milk.
Exists as:
- Monomer in serum
- Dimeric secretory IgA in secretions, joined by a J chain and protected by a secretory component.
Subclasses: IgA1 and IgA2.
Functions:
- Provides the first line of defense at respiratory, gastrointestinal, and genitourinary mucosa.
- Neutralizes viruses, bacteria, and toxins before they enter tissues.
- In breast milk, protects an infant's gastrointestinal tract from colonization and infection.
- Helps prevent viral binding to respiratory and gastrointestinal epithelium.

Sources: Jawetz, Melnick & Adelberg's Medical Microbiology, p. 81-85; Harrison’s Principles of Internal Medicine, p. 1575-1578.

3. Immunoglobulin M (IgM)

The first antibody produced after initial exposure to an antigen, so it is characteristic of the primary immune response.
Secreted IgM is a large pentamer joined by a J chain, giving it up to 10 antigen-binding sites.
As a monomer, it is present with IgD on mature B-cell surfaces as an antigen receptor.
Functions:
- The most efficient immunoglobulin for activating the classical complement pathway. One antigen-bound pentamer can initiate complement activation.
- Strongly promotes agglutination because of its multivalent structure.
- Important in defense against polysaccharide antigens on bacterial surfaces.
- Promotes opsonization, phagocytosis, and bacteriolysis indirectly through complement.
Because of its large size, IgM is largely confined to the intravascular compartment.

Source: Medical Microbiology 9e, p. 2676-2678.

4. Immunoglobulin D (IgD)

Found in very low concentrations in serum.
Primarily expressed on the surface of mature naïve B lymphocytes, along with IgM.
IgM and IgD on the same B cell have the same antigen specificity but different heavy-chain constant regions.
Functions:
- Acts as a B-cell antigen receptor.
- Participates in activation, maturation, proliferation, and differentiation of B cells.
- May help regulate B-cell responsiveness and tolerance.
Its exact role in the immune response is less clearly defined than that of the other immunoglobulin classes.

Source: Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 1424-1426.

5. Immunoglobulin E (IgE)

Present in very small amounts in serum.
Binds with high affinity to FcεRI receptors on mast cells and basophils.
Functions:
- Mediates type I immediate hypersensitivity reactions, including allergic rhinitis, urticaria, asthma, and anaphylaxis.
- On repeat exposure to an allergen, allergen cross-linking of mast-cell-bound IgE causes mast cell and basophil degranulation.
- This releases mediators such as histamine and leukotrienes, producing allergic symptoms.
- Important in immunity against helminths (parasitic worms), partly through eosinophil-associated responses.

Sources: K. J. Lee’s Essential Otolaryngology, p. 1380-1411; Medical Microbiology 9e, p. 2658-2666.

Easy mnemonic: GAMED

G - IgG: Goes across placenta; gives long-term systemic protection
A - IgA: at mucosal Areas and in secretions
M - IgM: Made first; Massive pentamer; strongest complement activator
E - IgE: Eosinophils, allergy, and parasites
D - IgD: B-cell Development and receptor function

Define Autoimmunity & Describe its Mechanisms

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Definition of autoimmunity

Autoimmunity is an immune response directed against the body’s own antigens, caused by activation of self-reactive T lymphocytes, B lymphocytes, or both.

Normally, the immune system is self-tolerant: it recognizes foreign antigens but does not attack self. Autoimmunity results when this tolerance fails.

Autoimmunity is not always autoimmune disease. Autoantibodies or self-reactive lymphocytes may occur without tissue injury. An autoimmune disease develops when the autoimmune response causes clinically significant inflammation, cellular dysfunction, or tissue destruction.

Mechanisms of autoimmunity

Autoimmunity usually arises through the interaction of:

Genetic susceptibility
Failure of self-tolerance
Environmental trigger, commonly infection, tissue injury, drugs, or altered self-antigens
Persistent immune-mediated tissue damage

1. Failure of self-tolerance

Self-reactive lymphocytes are normally controlled by central and peripheral tolerance mechanisms.

A. Defective central tolerance

Central tolerance occurs during lymphocyte development:

T cells mature in the thymus. Strongly self-reactive T cells are normally deleted by apoptosis, and some become regulatory T cells (Tregs).
B cells mature in bone marrow. Self-reactive immature B cells may undergo:
- Receptor editing: change their antigen receptor specificity
- Deletion: apoptosis of strongly self-reactive cells
- Anergy: functional inactivation

Failure of these processes allows autoreactive T or B cells to leave the thymus or bone marrow and enter the circulation.

Cellular and Molecular Immunology, Chapter 15, p. 3414-3429.

B. Defective peripheral tolerance

Self-reactive cells that escape central tolerance are normally kept inactive in peripheral tissues by:

Anergy: antigen recognition without adequate co-stimulation makes lymphocytes unresponsive.
Deletion: repeated stimulation may cause apoptosis, including Fas-mediated death.
Suppression by regulatory T cells: Tregs suppress autoreactive lymphocytes through inhibitory cytokines and cell-contact mechanisms.
Immune ignorance: certain self-antigens are normally inaccessible, present in too low an amount, or not presented with sufficient co-stimulation.

Breakdown of any of these peripheral control mechanisms can activate autoreactive lymphocytes.

Janeway’s Immunobiology 10e, p. 2419.

2. Genetic susceptibility

Some individuals inherit genes that increase the likelihood of loss of tolerance.

The strongest associations are often with particular HLA alleles, because HLA molecules determine which peptides are presented to T cells.
Certain HLA types may present self-peptides more effectively, allowing activation of autoreactive T cells.
Genes affecting lymphocyte activation, apoptosis, cytokine signaling, antigen clearance, and Treg function can also increase risk.

Examples include associations of particular HLA types with type 1 diabetes mellitus, celiac disease, ankylosing spondylitis, systemic lupus erythematosus, and other autoimmune disorders.

Goodman & Gilman’s The Pharmacological Basis of Therapeutics, p. 248-254.

3. Release of sequestered or hidden self-antigens

Some self-antigens are normally hidden from the immune system in immune-privileged sites, such as:

Eye
Testis
Central nervous system

Trauma, infection, inflammation, or surgery may expose these previously sequestered antigens. Since tolerance may not have developed against them, they can provoke an immune response.

Example: After trauma to one eye, immune responses to ocular antigens may damage both eyes, termed sympathetic ophthalmia.

4. Altered self-antigens or neoantigen formation

A normal self-protein can be altered by:

Drugs or drug metabolites
Chemicals
Infection
Radiation or tissue injury
Post-translational changes, such as citrullination

The altered self-protein may appear foreign and stimulate T cells and antibodies. The immune reaction can then cross-react with normal tissue.

Example: Some drugs bind host proteins and act as haptens, making the protein immunogenic.

5. Molecular mimicry

Molecular mimicry occurs when a microbial antigen resembles a host antigen structurally or antigenically.

An immune response against the pathogen then cross-reacts with similar self-antigens, leading to tissue injury.

Examples:

Rheumatic fever: antibodies and T cells generated against group A streptococcal antigens cross-react with cardiac tissue.
Guillain-Barré syndrome: antibodies formed after Campylobacter jejuni infection may cross-react with peripheral nerve gangliosides.

Molecular mimicry is most likely to produce disease in a genetically susceptible person and in the setting of inflammation.

Tietz Textbook of Laboratory Medicine, p. 2963; Goodman & Gilman’s The Pharmacological Basis of Therapeutics, p. 248-254.

6. Bystander activation

During infection or tissue damage, inflammation produces cytokines, upregulates co-stimulatory molecules on antigen-presenting cells, and causes tissue-cell injury.

This inflammatory setting may activate nearby autoreactive T cells non-specifically, even if their specific self-antigen was not the original trigger. This is called bystander activation.

Infections may therefore break peripheral tolerance by creating an environment rich in co-stimulation and inflammatory cytokines.

7. Epitope spreading

Initially, an autoimmune response may target one self-epitope. Tissue destruction then releases additional self-antigens, producing immune responses against new epitopes.

This expansion of the autoimmune response is termed epitope spreading.

It establishes a vicious cycle:

Initial autoimmune response causes inflammation and tissue injury.
Damaged cells release more self-antigens.
New autoreactive T and B cells become activated.
The disease becomes broader, more persistent, and more severe.

Cellular and Molecular Immunology, p. 1680-1686; Harrison’s Principles of Internal Medicine 22E, p. 908-911.

8. Defective clearance of apoptotic cells and immune complexes

Normally, apoptotic cells and cellular debris are removed rapidly, preventing exposure of intracellular antigens.

Defective clearance can lead to prolonged exposure of nuclear and cytoplasmic antigens. These antigens may be taken up by antigen-presenting cells and stimulate autoreactive B and T cells.

This mechanism is particularly relevant in systemic lupus erythematosus, where antibodies may develop against nuclear antigens such as DNA, histones, and ribonucleoproteins.

How autoimmune injury occurs

Once tolerance is lost, tissue damage may result through three main immune mechanisms:

Mechanism	How injury occurs	Example
Autoantibody-mediated injury	Antibodies bind cell or tissue antigens, activate complement, opsonize cells, or alter receptor function	Autoimmune hemolytic anemia, myasthenia gravis, Graves disease
Immune-complex injury	Antigen-antibody complexes deposit in tissues and trigger inflammation	Systemic lupus erythematosus
T-cell-mediated injury	Cytotoxic T cells destroy target cells, or helper T cells activate macrophages and inflammation	Type 1 diabetes mellitus, multiple sclerosis

Summary flowchart

Genetic predisposition

failure of central/peripheral tolerance
environmental trigger such as infection, trauma, drug, or tissue injury
↓
Activation of autoreactive T cells and B cells
↓
Autoantibody formation, immune-complex deposition, or T-cell-mediated inflammation
↓
Tissue damage and release of additional self-antigens
↓
Epitope spreading and chronic autoimmune disease

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