Dr. Hafeez- Immunoglobulins (Structure & Functions)
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Transcript of Dr. Hafeez- Immunoglobulins (Structure & Functions)
Immunoglobulins:Structure and Function
Immunoglobulins:Structure and Function
• Definition: Glycoprotein molecules that are produced by plasma cells in response to an immunogen and which function as antibodies
Immune serum
Ag adsorbed serum
1 2
+ -
albumin
globulins
Mobility
Am
oun
t of
pro
tein
General Functions of Immunoglobulins
• Effector functions – Fixation of complement– Binding to various cells
(Usually require Ag binding)
• Ag binding– Can result in protection– Valency
Basic Immunoglobulin Structure
• Immunoglobulins - heterogeneous
• Myeloma proteins - homogeneous immunoglobulins
Immunoglobulin Structure
• Heavy & Light Chains
• Disulfide bonds– Inter-chain– Intra-chain
CH1
VL
CL
VH
CH2 CH3
Hinge Region
Carbohydrate
Disulfide bond
Immunoglobulin Structure
• Variable & Constant Regions– VL & CL
– VH & CH
• Hinge RegionCH1
VL
CL
VH
CH2 CH3
Hinge Region
Carbohydrate
Disulfide bond
Immunoglobulin Structure
• Domains– VL & CL
– VH & CH1 - CH3 (or CH4)
• Oligosaccharides CH1
VL
CL
VH
CH2 CH3
Hinge Region
Carbohydrate
Disulfide bond
IgG molecule
Structure of the Variable Region
• Hypervariable (HVR) or complimentarity determining regions (CDR)
HVR3
FR1 FR2 FR3 FR4
HVR1HVR2
Var
iabi
lity
Ind
ex
25 7550 100Amino acid residue
150
100
50
0
• Framework regions
IMMUNOGLOBULIN
Immunoglobulin Fragments: Structure/Function Relationships
• Fab– Ag binding– Valence = 1– Specificty
determined by VH and VL
Papain
Fc
Fab
• Fc– Effector functions
Immunoglobulin Fragments: Structure/Function Relationships
Ag Binding
Complement Binding Site
Placental Transfer
Binding to Fc Receptors
Immunoglobulin Fragments: Structure/Function Relationships
• Fab– Ag binding
• Fc– Effector functions
• F(ab’)2
Pepsin
Fc Peptides
F(ab’)2
Human Immunoglobulin Classes
Difference in amino acid sequence
in the C-region of H-chains
• IgG - Gamma (γ) heavy chains
• IgM - Mu (µ) heavy chains
• IgA - Alpha (α) heavy chains
• IgD - Delta (Δ) heavy chains
• IgE - Epsilon (ε) heavy chains
CH
1
VL
CL
VH
CH
2 C
H3
Hin
ge Region
Carb
ohyd
rate
Disu
lfide b
ond
Human Immunoglobulin SubclassesSmall difference in amino acid sequence
in the C-region of H-chains
• IgG Subclasses– IgG1 - Gamma 1 (γ 1) heavy chains– IgG2 - Gamma 2 (γ 2) heavy chains– IgG3 - Gamma 3 (γ 3) heavy chains– IgG4 - Gamma 4 (γ 4) heavy chains
• IgA subclasses– IgA1 - Alpha 1 (α 1) heavy chains– IgA2 - Alpha 2 (α 2) heavy chains
Human ImmunoglobulinLight Chain Types
Difference in amino acid sequence
in the C-region of L-chains
• Kappa (κ)
• Lambda (λ)
Human ImmunoglobulinLight Chain Subtypes
• Lambda light chains– Lambda 1 (λ 1)– Lambda 2 (λ 2)– Lambda 3 (λ 3) – Lambda 4 (λ 4)
Immunoglobulins
• Nomenclature– IgM (κ)– IgA1(λ 2)– IgG
• Heterogeneity
IgG
• Structure– Monomer (7S)
IgG1, IgG2 and IgG4 IgG3
IgG
• Structure• Properties
– Major serum Ig– Major Ig in extravascular spaces– Placental transfer – Does not require Ag
binding (α IgG2)– Fixes complement (α IgG4)– Binds to Fc receptors (α IgG2, IgG4)
• Phagocytes - opsonization• K cells - ADCC
• Increases in:
a) Chronic granulomatous infectionsb) Infections of all typesc) Hyperimmunizationd) Liver diseasee) Malnutrition (severe)f) Dysproteinemiag) Disease associated with hypersensitivity granulomas, dermatologic disorders, and IgG myelomah) Rheumatoid arthritis
• Decreases in:
a) Agammaglobulinemiab) Lymphoid aplasiac) Selective IgG, IgA deficiencyd) IgA myelomae) Bence Jones proteinemiaf) Chronic lymphoblastic leukemia
IgM
• Structure– Pentamer (19S)
– Extra domain (CH4)
– J chainC4
J Chain
IgM
• Structure
• Properties– 3rd highest serum Ig– First Ig made by fetus
and B cells– Fixes complement
Fixation of C1 by IgG and IgM Abs
C1r C1s
C1qC1r C1s
C1q
No activation Activation
IgM
• Structure
• Properties– 3rd highest serum Ig– First Ig made by fetus
and B cells– Fixes complement
Tail Piece
– Agglutinating Ig– Binds to Fc receptors– B cell surface Ig
B Cell Antigen Receptor (BcR)
Ig- αIg- α Ig-Ig-
• Increases (in adults) in:
a) Waldenström's macroglobulinemiab) Trypanosomiasisc) Actinomycosisd) Carrión's disease (bartonellosis)e) Malariaf) Infectious mononucleosisg) Lupus erythematosush) Rheumatoid arthritisI) Dysgammaglobulinemia (certain cases)
In the newborn, a level of IgM above 20 ng./dl is an indication of in utero stimulation of the immune system and stimulation by the rubella virus, the cytomegalovirus, syphilis, or toxoplasmosis.
• Decreases in:
a) Agammaglobulinemiab) Lymphoproliferative disorders (certain cases)c) Lymphoid aplasiad) IgG and IgA myelomae) Dysgammaglobulinemiaf) Chronic lymphoblastic leukemia
IgA
• Structure– Serum - monomer– Secretions (sIgA)
• Dimer (11S)
• J chain
• Secretory component
J ChainSecretory Piece
Origin of Secretory Component of sIgA
IgA
• Structure
• Properties– 2nd highest serum Ig– Major secretory Ig (Mucosal or Local Immunity)
• Tears, saliva, gastric and pulmonary secretions
– Does not fix complement (unless aggregated)– Binds to Fc receptors on some cells
• Increases in:
a) Wiskott-Aldrich syndromeb) Cirrhosis of the liver (most cases)c) Certain stages of collagen and other autoimmune disorders such as rheumatoid arthritis and lupus erythematosusd) Chronic infections not based on immunologic deficienciese) IgA myeloma
• Decreases in:
a) Hereditary ataxia telangiectasiab) Immunologic deficiency states (e.g., dysgammaglobulinemia, congenital and acquired agammaglobulinemia, and hypogammaglobulinemia)c) Malabsorption syndromesd) Lymphoid aplasiae) IgG myelomaf) Acute lymphoblastic leukemiag) Chronic lymphoblastic leukemia
IgD
• Structure– Monomer– Tail piece
Tail Piece
IgD
• Structure
• Properties– 4th highest serum Ig– B cell surface Ig– Does not bind complement
• Increases in:
a) Chronic infectionsb) IgD myelomas
IgE
• Structure– Monomer
– Extra domain (CH4)
C4
IgE
• Structure• Properties
– Least common serum Ig• Binds to basophils and mast cells (Does not require
Ag binding)
– Allergic reactions– Parasitic infections (Helminths)
• Binds to Fc receptor on eosinophils
– Does not fix complement
• Increases in:
a) Atopic skin diseases such as eczemab) Hay feverc) Asthmad) Anaphylactic shocke) IgE-myeloma
• Decreases in:
a) Congenital agammaglobulinemiab) Hypogammaglobulinemia due to faulty metabolism or synthesis of immunoglobulins
IgDiv1
IgDiv2
IgDiv3