Immunoglobulins: Structure and Function | Zoology Optional Notes for UPSC PDF Download

Definition

Immunoglobulin (Ig):

• Glycoprotein molecules produced by plasma cells in response to immunogens.
• Named for their migration with globular proteins in an electric field.

General Functions of Immunoglobulins

A. Antigen Binding:

• Immunoglobulins bind specifically to antigens.
• Each antibody binds to a specific antigenic determinant.
• Valency refers to the number of antigenic determinants an antibody can bind.

B. Effector Functions:

1. Fixation of Complement:
   • Results in cell lysis and release of biologically active molecules.
2. Binding to Various Cell Types:
   • Receptors on phagocytic cells, lymphocytes, platelets, mast cells, and basophils.
   • Facilitates immunity transfer to fetus/newborn through placental trophoblasts.

Basic Structure of Immunoglobulins

1. Heavy and Light Chains:

• Four-chain structure: Two identical light chains (23kD) and two identical heavy chains (50-70kD).

2. Disulfide Bonds:

1. Inter-chain Disulfide Bonds:
   • Hold heavy and light chains together.
   • Varies among different immunoglobulin molecules.
2. Intra-chain Disulfide Bonds:
   • Present within each polypeptide chain.

3. Variable (V) and Constant (C) Regions:

1. Light Chain:
   • VL (110 amino acids) and CL (110 amino acids).
2. Heavy Chain:
   • VH (110 amino acids) and CH (330-440 amino acids).

4. Hinge Region:

• Allows flexibility in the antibody molecule.

5. Domains:

• Three-dimensional folded regions with intra-chain disulfide bonds.

1. Light Chain Domains:
   • VL and CL.
2. Heavy Chain Domains:
   • VH, CH1 - CH3 (or CH4).

6. Oligosaccharides:

• Carbohydrates attached to the CH2 domain in most immunoglobulins.

Structure of the Variable Region

• Three regions with high variability in amino acid sequences.
• Responsible for the specificity of antibodies.

B. Framework Regions:

• Regions between CDRs in the variable region.
• Divide immunoglobulin variable regions into groups and subgroups.

V. Immunoglobulin Fragments: Structure/Function Relationships

A. Fab:

• Produced by papain digestion, contains antigen-binding sites.
• Monovalent; combining site created by both VH and VL.

B. Fc:

• Produced by papain digestion, contains the remainder of heavy chains.
• Mediates effector functions; different domains mediate different functions.

C. F(ab')2:

• Produced by pepsin digestion, contains both antigen-binding sites.
• Divalent; does not mediate effector functions.

Human Immunoglobulin Classes, Subclasses, Types, and Subtypes

I. Immunoglobulin Classes

• Most abundant immunoglobulin in serum.
• Involved in secondary immune responses.
• Subdivided into four subclasses: IgG1, IgG2, IgG3, IgG4.

• First antibody produced during primary immune responses.
• Efficient in agglutination and complement activation.

• Predominantly found in secretions like saliva and breast milk.
• Subdivided into two subclasses: IgA1, IgA2.

• Found on the surface of B cells.
• Exact function not fully understood.

• Involved in allergic responses and defense against parasitic infections.
• Triggers histamine release from mast cells.

II. Immunoglobulin Subclasses

• a) IgG1: Predominant in serum, effective against bacteria and viruses.
• b) IgG2: Effective against polysaccharide antigens, important in bacterial defense.
• c) IgG3: Efficient in fixing complement, plays a role in viral defense.
• d) IgG4: Involved in modulation of immune responses, less effective in complement activation.

2. IgA Subclasses

• a) IgA1: Predominant in serum, found in the blood.
• b) IgA2: Predominant in mucosal secretions, found in saliva and breast milk.

III. Immunoglobulin Types

• One of the two types of light chains.
• Detected serologically.

2. Lambda Light Chains

• The other type of light chain.
• Detected serologically.

IV. Immunoglobulin Subtypes

• a) Lambda 1
• b) Lambda 2
• c) Lambda 3
• d) Lambda 4

V. Nomenclature

• Immunoglobulins are named based on the class or subclass of the heavy chain and type or subtype of the light chain.
• Unless stated precisely, assume all subclasses, types, and subtypes are present (e.g., IgG implies the presence of all IgG subclasses and types).

VI. Heterogeneity

• Immunoglobulins are heterogeneous due to different classes, subclasses, types, and subtypes of heavy and light chains.
• Variability in VH and VL regions contributes to different antigen-binding properties

Structure and Properties of Ig Classes and Subclasses

• Monomers (7s immunoglobulin).
• Subclasses differ in disulfide bonds and hinge region length.

• Major serum Ig (75% of serum Ig is IgG).
• Major Ig in extra vascular spaces.
• Placental transfer: Only Ig that crosses the placenta; subclasses cross differently.
• Complement fixation: Not all subclasses fix complement equally.
• Binding to cells: Fc receptors on various cells; subclasses differ in binding.

Structure

• Normally pentamer (19s immunoglobulin) but can exist as a monomer.
• Identical heavy and light chains in the pentameric form.
• Extra domain on mu chain (ch4) and J chain in the pentameric form.

• Third most common serum Ig.
• First Ig produced by the fetus and virgin B cells.
• Efficient complement fixing and agglutinating Ig.
• Binds to some cells via Fc receptors.
• Surface IgM on B cells acts as a receptor for antigens.

• Serum IgA is a monomer; secreted IgA is a dimer with a J chain and secretory piece.
• Secretory piece added in epithelial cells during secretion.

• Second most common serum Ig.
• Major Ig in secretions (tears, saliva, colostrum, mucus).
• Secretory IgA important in local (mucosal) immunity.
• Normally does not fix complement unless aggregated.
• Can bind to some cells (PMNs and some lymphocytes).

Structure

• Exists only as a monomer.

• Found in low levels in serum; role uncertain.
• Found primarily on B cell surfaces as a receptor for antigens.
• Does not bind complement.

• Monomer with an extra domain in the constant region.

• Least common serum Ig.
• Involved in allergic reactions by binding to basophils and mast cells.
• Plays a role in parasitic helminth diseases.
• Does not fix complement.

Clinical Implications of Human Immunoglobulin Classes

IgG:

1. Increases in: a) Chronic granulomatous infections b) Infections of all types c) Hyperimmunization d) Liver disease e) Severe malnutrition f) Dysproteinemia g) Diseases associated with hypersensitivity granulomas, dermatologic disorders, and IgG myeloma h) Rheumatoid arthritis

2. Decreases in: a) Agammaglobulinemia b) Lymphoid aplasia c) Selective IgG, IgA deficiency d) IgA myeloma e) Bence Jones proteinemia f) Chronic lymphoblastic leukemia

1. Increases (in adults) in: 
   • Waldenström's macroglobulinemia 
   • Trypanosomiasis
   • Actinomycosis 
   • Carrión's disease (Bartonellosis) 
   • Malaria
   • Infectious mononucleosis 
   • Lupus erythematosus 
   • Rheumatoid arthritis 
   • Dysgammaglobulinemia (certain cases)
2. Note: In newborns, IgM levels above 20 ng./dl indicate in utero immune system stimulation and stimulation by rubella virus, cytomegalovirus, syphilis, or toxoplasmosis.
3. Decreases in: 
   • Agammaglobulinemia 
   • Lymphoproliferative disorders (certain cases) 
   • Lymphoid aplasia 
   • IgG and IgA myeloma 
   • Dysgammaglobulinemia 
   • Chronic lymphoblastic leukemia

1. Increases in: 
   • Wiskott-Aldrich syndrome 
   • Cirrhosis of the liver (most cases) 
   • Certain stages of collagen and other autoimmune disorders such as rheumatoid arthritis and lupus erythematosus 
   • Chronic infections not based on immunologic deficiencies 
   • IgA myeloma
2. Decreases in: 
   • Hereditary ataxia telangiectasia
   • Immunologic deficiency states (e.g., dysgammaglobulinemia, congenital and acquired agammaglobulinemia, and hypogammaglobulinemia) 
   • Malabsorption syndromes 
   • Lymphoid aplasia 
   • IgG myeloma
   • Acute lymphoblastic leukemia
   • Chronic lymphoblastic leukemia

1. Increases in: 
   • Chronic infections
   • IgD myelomas

1. Increases in: 
   • Atopic skin diseases such as eczema 
   • Hay fever
   • Asthma 
   • Anaphylactic shock
   • IgE-myeloma
2. Decreases in: 
   • Congenital agammaglobulinemia
   • Hypogammaglobulinemia due to faulty metabolism or synthesis of immunoglobulins