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Prof Anura Weerasinghe MBBS(Col), MD(Col), DCH(Col), DTM&H(Col), FRCP(UK), PhD(Japan) Professor of Physiology Faculty of Medicine University of Kelaniya
Challenges
External
Microbes Allergens
Internal
Autoantigens Cancer cells Transplantation antigens
Genetic factors
Ankylosing spondylitis B27 Reiters disease B27 Juvenile diabetes mellitus DR3/DR4
Infections
EBV, mycoplasma, streptococci, klebsiella, Borrelia, malaria
Drugs
Procainamide
Chemical
Diaoxin
Biological
HBV -Herpes simplex - HTLV EBV - Papilloma virus
Tumour antigens
Virally or chemically induced tumour antigens
RNA
HTLV
DNA
EBV Human pailloma virus Hepatitis B virus Shared by all tumours induced by the same virus
Oncofoetal antigens
CEA and AFP
Transplantation antigens
Blood group antigens
ABO system
Allograft
Kidney, Heart (heart/lung), pancreas, cornea, bone marrow, liver and blood
Communication
Direct; cell to cell contact Indirect; through mediators eg; Cytokines
Battle
With cells or molecules
Disposal
With cells or molecules
Molecules
Complements, cytokines, APP(CRP)
APCs
Macrophages
Langerhans cells in skin Dendritic cells
FDC
Presentation to B cells in the follicular region
IDD
Presentation to T cells in the parafollicular region
B cells
Lymphoid organs
Primary
Bone marrow Thymus
Secondary
Mucosa related
Bronchial, gastrointestinal and Gumucosa
Communication
Direct
MHC dependent
MHC class I CD8 MDC class II CD4
MHC independent
NK cells Macrophages
Indirect
Molecules
Cytokines
Classification of MNCs
Morphological Phenotypical
CD4
T cells - CD2, 3, 5 & 7 CD8 B cells CD19 & 20 NK cells CD 16, 56 & 57 Monocytes CD 33
- DTH - Cytotoxic
Functional
Memory Th1 & Th2
Molecular biological
Further classification of + T lymphocytes CD4 IL-2 Th1 INF- CD4 Th2 IL-4
Antibodies (Immunoglobulins)
Discovered by Paul Ehrlich (1854 1915)
Shared Nobel Prize with Metchnikoff for their work on immunity in 1908
Glycoproteins Present in gammaglobulin fraction of serum Some pass through physiological barriers
Synthesized by plasma cells Distributed in both intra and extravascular compartments React specifically with antigens in vivo and in vitro
Immunoglobulin structure
VH CH3 CH2 CH1 VL
Immunoglobulin structure
Heavy (H) chains
MW 50 70 kDa 400 amino acids Amino acid differences determine the isotypes Thus, 5 classes of Igs Allotypes determine the
Antibody units
All antibodies have the same basic four polypeptide chain unit: two light (L) chains and two heavy (H) chains. There are five different kinds of H-chains ( , , , and ), which determine the class of antibody (IgM, IgD, IgG, IgE and IgA respectively). There are also two different kinds of L-chains - and . Each antibody unit can have only or Lchains but not both.
180
190
1.4 4.0 6
IgG
+
IgA
_ _ _
IgM
+++ _ _
IgD
_ _ _
IgE
_ +++ _
IgA
Two forms; serum/ secretory Dimeric Two subtypes IgA2 is more important in mucosal immunity Half lie ; 6 days Dose not bind complement via classical pathway
Serum IgA
15 20% of total
Secretory IgA
Predominat Ig in secretions Dominant subclass is sIgA2 Secretory component is synthesized by exocrine epithelia cells Opsonize foreign particles; PMNs have Fc (IgA) receptor
IgG
75% of total normal serum Ig 1200 mg/dl Major Ab in secondary immune respnse Monomer Four subclasses Only Ig that cross placenta (secretory IgA in colostrum) Ig, except IgG4 binds complements by the classical pathway Antitoxic immunity Major opsonizing Ig
IgM
10% of Ig (120mg/dl) Pentameric structure Half-life; 10 days Predominant antibody in primary immune response Monomeric form appear in the B-cell membrane Predominant antibody produced by the foetus Only antibody made to certain carbohydrate Ag (eg; ABO) Most efficient Ig activating complements Not intrinsically opsonic but through complements Secretory IgM (Parotid glands)
IgD
Less than 1% (3-5 mg/dl) Monomer Occurs in large quantities on the Bcell membrane Half-life; 2-3 days Involve as an Ag receptor in B cell activation
IgE
0.005% of Ig (0.05 mg/dl) Heat-labile at 500C Monomer with 5 damains in heavy chain (as in IgM) Half-life: 2-3 days Dose not cross the placenta; production begins early in gestation Associated with atopic disease Fixation to mast cells and basophils via FcR On activation with allergen release mediators of atopic disease Immunity to certain helminthic parasites Unable to activate complement
Immune response
Immunogen
APC
B
T
PC
CMI Humoral
Indirect
IL-4 facilitates class switching INF- inhibits class switching
IgM 10 20 30 40 50 Days
2 4 6 8 Time(months)
Alternate
Microbial polysaccharides such as endotoxin IgA
Classical
C3 Convertase (C4b2a)
Alternate
C3 Convertase (C3bBbP)
Alternate
Factor I Factor H
Opsonization
C3b
Angio-oedema
Hereditary or acquired C1esterase inhibitor deficiency Acute attack of angio-oedema usually follow minor trauma Increased vascular permeability Low C4 and high C3 C1esterase inhibitor level is low
Reduction
Albumin Transferrin
C-reactive protein
Observed about 60 years ago The sera of patients with acute febrile illness contained a substance that caused the precipitation of polysaccharide extractable from the cell wall of Strep. Pneumoniae (fraction C).
Physiological properties
Synthesized by hepatocytes Elevated in pregnancy Does not cross the placenta Promote macrophage phagocytosis by activating classical complement pathway Enhance cytotoxic T-cell response
Clinical significance
Non-specific Marker of well person Bacterial>fungal>parasitic>viral Indicate infection in SLE and malignancy Useful in monitoring in Rheumatoid arthritis and Rheumatic fever not affected by anti-inflammatory drugs
Cytokines
Small molecules with multiple functions Same cytokine can be made by different cell types (eg. INF produced by T cells and NK cells) may have different effects on different cell populations (eg activate macrophages to kill intracellular microbes and B cells to undergo antibody class switching)
Functions of cytokines
Signal between cells induce growth & differentiation Chemotaxis Enhance cytotoxicity Regulation of immunity
Cytokine nomenclature
Interleukins
produced by leukocytes
Monokines
produced by myeloid cells
Lymphokines
produced by lymphocytes
Cytokine nomenclature
Cheamokines
direct cell migration activate cells
Interferons
activation & modulation of immunity defense against viral infection
Type I
Interferons
INF - produced by leukocytes INF - produced by fibroblasts inhibit viral replication & cell proliferation increase NK cell lytic activity modulate MHC expression
increase expression of MHC class I
Interferons
Type II
INF - produced by Th1 cells & NK cells activates macrophages & PMNs for enhanced killing induces the development of Th1 cells that are critical to CTL & IgG production
Lymphokines
Growth factors for lymphocytes
IL-2 by T cells ---> Th1 IL-4 by T cells --> Th2 --> B cells class switch to IgE
Monokines
Activities critical to immune defence & inflammation
IL-1, TNF- & IL-6
activates Macrophages & vascular endothelium increase body tempreture
IL-8
Chemotaxis of PMNs
IL-12
activates NK cells to produce INF-
Chemokines
Activate and direct effector cells to sites of tissue damage Regulate lymphocyte migration into tissues
Other cytokines
CSF drive the development, differenciation & expansion of cells of the myeloid series GM-CSF induces commitment of progenitor cells to the monocyte /granulocyte lineage
Inhibit viral replication Induce expression of MHC class II Increase expression of Fc receptor on macrophages Activate macrophages for microcidal and tumoricidal activity Inhibit cell growth Enhance the activity of NK cells Inhibit class switching to IgE synthesis
Enhance
IL-12 INF- IL-4 IL-10
Tho
Cytokines produced Effect Help for CTL INF- and IgG IL-2 antibody response
IL-4 IL-6 IL-13 IL-5 IL-10 Help for IgA and IgE antibody response
Th2
enhance haemopoesis
G-CSF
Rx of low PMN counts resulting from chaemotherapy or irradiation
Autoimmunity
Original Classification of hypersensitivity by Gell and Coombs Type Immune mechanisms I IgE antibodies II Ab & complement III Ag/Ab complexes IV T cell mediated
Type V
Time of appearance
Type I Type II (Cytotoxic) Type III (Immune complex) Type IV 2 to 30 minutes (immediate) 5 to 8 hours (Intermediate) 2 to 8 hours (Intermediate) 24 72 hours (delayed)
Cytokines
B cell
IL-4
IgE Mast cell Allergen IL-5
Type II hypersensitivity
Cytotoxic hypersensitivity IgG and IgM mediated Antibodies are directed mainly to cellular antigens (e.g. on erythrocytes) or surface autoantigens Causes damage through opsonization, lysis or antibody dependent cellular cytotoxicity
Transfusion reactions
Isohaemaglutinins against major blood group antigens (A & B)
Autoantigens
Basement membranes of lung & kidney Goodpastures syndrome Acetylcholine receptor Myasthenia gravis Erythrocytes Haemolytic anaemia
Inhalation of bacterial spores Farmers lung Avian serum/faecal proteins Bird fanciers lung
Systemic damage:
Serum sickness Vasculitis Post streptococcal glomerulonephritis
Type IV hypersensitivity
Delayed type (Occurs 24 hours after contact with antigens) Mediated by cells (T cells together with dendritic cells, macrophages and cytokines) Persistence presence of antigen leads to the formation of granuloma
Autoimmunity
Autoimmunity is acquired immune reactivity to self antigens. Autoimmune diseases occur when autoimmune responses lead to tissue damage. Mechanisms of development Factors contributing to the development of autoimmune disease The spectrum and prevalence of autoimmunity Principles of treatment
Immunologic Tolerance
The unresponsiveness of the immune system to self-antigen. Autoimmunity results from failure of mechanisms responsible for immunologic tolerance.
Gender
Women have a greater risk than in men
Neuroendocrine system influence Male:Female SLE 10:1 Graves disease 7:1 Ankylosing spondylitis is almost exclusively a male disease
Genetic factors Disease Ankylosing spondylitis Reiters disease SLE Myasthenia gravis IDDM Psoriasis Multiple sclerosis Rheumatoid arthritis
Infections
Eg; EBV, Mycoplasma, Streptococci, Borrelia burgdoferi (Lyme arthritis) and malaria
Drugs
Eg; Procainamide (10% develop SLE like syndrome)
Immunodeficiency
Eg: C2, C4, C5, C8 & IgA deficiency
Polyendocrine
Multiple endocrine organs
- IgG (Rheumatoid factor) Scleroderma - nuclei & centromeres SLE - dsDNA Wegerners granulomatosis Cytoplasm of the neutrophils PAN - Cytoplasm of the neutrophils
Autoimmune response
Humoral factors
Antibodies Immune complexes
Vasculitis Guillan-Barre syndrome
Cellular factors
Metabolic control
Principles of treatment
Immune modulators
NSAID SAID Immunosuppressive cytotoxic drugs
Immunology of Transplantation
Immune Response to graft cells Immunology of graft dysfunction Strategies to prevent rejection Treatment of acute rejection
APC
T cell
T cell
Humoral rejection
Antigen antibody Complexes
Activation of Complement cascade Chemotaxis & Inflammation
Occlusion of capillaries & prevent vascularization
Antilymphocyte globulin
IV ALG for 7 to 10 days
OKT3
5 mg IV for 10 to 14 days
Classification of immunodeficiencies
Primary usually congenital (inherited)
The result of a failure of proper development of the humoral or cellular immune system
Secondary acquired
The consequences of other diseases (eg; AIDs) and treatments.
Primary immunodeficiency
Complement Phagocytes Humoral immunity Cellular immunity
Complement deficiency
C3 deficiency
Recurrent infections with encapsulated organisms
Pneumococcus, Streptococcus & Neisseria
C1, C2 or C4 deficiency
Immunecomplex diseases (Unable to remove Ag-Ab complexes)
Defective phagocytosis
Lack of fusion of phagosome with lysosomes
Chediak-Higashi syndrome
B cell deficiencies
Abnormal B cell maturation
Lack of Stem cells
Severe Combined Immunodeficiency (SCID)
B cell deficiencies
Severe Combined Immunodeficiency (SCID)
Functional impairment of both B and T lymphocyte limbs of the immune response. Inheritance is either X-linked or autosomal recessive
Brutons Agammaglobulinemia
X-linked inheritance
Result in recurrent viral, fungal, mycobacterial and protozoan infections Lack of Thymus
Di Georges syndrome
Cellular Immunodeficiency
DiGeorges syndrome
Failure of the parathyroids and thymus to develop normally from the third and fourth pharyngeal pouches Appearance of hypocalcemic tetany shortly after birth Occurs in both males and famales A number of physical abnormalities Wide set eyes (hyperteliorism) Antimongoloid slant of the eyes Low-set and notched ears Small jaw (micrognathia) Short philtrum of the upper lip Cardiac abnormalities (Tetralogy of Fallot)
Nezelofs syndrome
Cellular immunodeficiency with normal or increased immunoglobulins
Ataxia-Telangiectasia
Autosomal recessive disorder Ataxia Telangiectasia Recurrent sinopulmonary infections
Quantitate circulating B cells by flowcytometry Evaluate induction of B cell differentiation Evaluate the presence of B cells and plasma cells in lymph nodes (biopsy)
Evaluate lymphocyte proliferation to lectins (PHA & Con A) and alloantigens (MLR) Analyse T lymphocyte function
Lymphokine production; INF, IL-2 Cellular cytotoxicity
Quantitative estimation of individual complement components Assay neutrophil chemotaxis using C in patients serum as a chemoattractant