Immunology for SurgeryProf Anura Weerasinghe

MBBS(Col), MD(Col), DCH(Col), DTM&H(Col), FRCP(UK),

PhD(Japan)

Professor of Physiology

Faculty of Medicine

University of Kelaniya

Function of the Immune system

Protection of the body form challenges

Challenges

• External– Microbes– Allergens

• Internal– Autoantigens– Cancer cells– Transplantation antigens

Factors contributing to the development of autoimmune disease• Age and gender

– SLE 10:1, Grave’s disease 7:1

• Genetic factors– Ankylosing spondylitis B27– Reiter’s disease B27– Juvenile diabetes mellitus DR3/DR4

• Infections– EBV, mycoplasma, streptococci, klebsiella, Borrelia, malaria

• Drugs– Procainamide

Factors contributing to carcinogenesis

• Physical– UV light

• Chemical – Diaoxin

• Biological– HBV -Herpes simplex - HTLV– EBV - Papilloma virus

Damage occurs in the tumor suppressor gene or Pro-oncogene.

Tumour antigens• Virally or chemically induced tumour antigens

– RNA• HTLV

– DNA• EBV• Human pailloma virus• Hepatitis B virusShared by all tumours induced by the same virus

• Oncofoetal antigens– CEA and AFP

Transplantation antigens

• Blood group antigens– ABO system

• Major histocompatibility complex antigens– MHC class I ; A, B, C– MHC class II ; DP, DQ, DR

• Minor histocompatibility antigens– Non-ABO blood groups– Antigens associated with sex chromosomes– CD1

Types of tissue grafts• Autograft

– Skin & bone marrow

• Allograft– Kidney, Heart (heart/lung), pancreas, cornea,

bone marrow, liver and blood

• Xenograft

• Syngenic graft

Properties of the immune system• Recognition

– Distinguish self from non-self

• Communication– Direct; cell to cell contact– Indirect; through mediators eg; Cytokines

• Battle– With cells or molecules

• Disposal– With cells or molecules

Components of the immune system

• Innate– Physical, chemical & mechanical barriers– Cells

• Granulocytes, NK cells, Macrophages

– Molecules• Complements, cytokines, APP(CRP)

• Acquired (CMI or HI)– Cells & molecules

• Lymphocytes

• Immunoglobulin, cytokines & complements

APCs bridge the innate & acquired immune response.

APCs• Macrophages

– Langerhan’s 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

– Spleen– Lymph nodes

Natural Killer Cells• Large granular lymphocytes• 5-15% of peripheral lymphocytes• kill cells infected with viruses & tumour

cells• The mechanism of killing is identical to that

used by CTL– through the release of granules (perforins &

granzymes)– through FasL-Fas molecules

• NK cells secrete INF-gamma

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– T cells - CD2, 3, 5 & 7– B cells – CD19 & 20– NK cells – CD 16, 56 & 57– Monocytes – CD 33

• Functional– Memory - DTH - Cytotoxic– Th1 & Th2

• Molecular biological

CD4

CD8

Further classification of CD4+ T lymphocytes

CD4

Th1

Th2

IL-2 INF-

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

CH3 CH2CH1

VH

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

• Light (L) chains– 200 amino acids

– Two types; kappa and lambda

– All Igs have both k & l

– K to l is 3:2

Antibodies – basic structure• Antibodies are glycoproteins that bind antigens

with high specificity and affinity.• There are five chemical and physically distinct

classes of antibodies (IgG, IgA, IgM, IgD & IgE)• Affinity is the tightness of binding of an antibody

site to an antigenic determinant – the tighter the binding, the less likely the antibody is to dissociate from antigen. Antibodies produced by a memory response have higher affinity than those in a primary response.

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 L-chains but not both.

Physical properties of immunoglobulins

Physical properties

IgG IgA IgM IgD IgE

Molecular weight kD

150 170 - 420

900 180 190

Physiological properties of immunoglobulins

Physiological properties

IgG IgA IgM IgD IgE

Normal adult serum (mg/dl)

8 - 16

1.4 – 4.0

0.4 – 2.0

0.03 ngs

Half-life in days

23 6 5 3 <3

Biological properties of immunglobulins

Biological properties

IgG IgA IgM IgD IgE

Complement-fixing capacity

+ _ +++ _ _

Anaphylactic hypersensitivity

_ _ _ _ +++

Placental transport to fetus

+ _ _ _ _

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 B-cell 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

Immunoglobulin class switching(Isotype switching)

• During the immune response, plasma cells switch from producing IgM to IgG or to another immunoglobulin class (IgA or IgE)

• No change in antigen-binding specificity• Switch involves a change in the H-chain

constant damains• H-chain gene rearrangement permit isotype

switching

Protective mechanisms of antibodies

• Neutralization of bacteria

• Prevent viral and bacterial entry

• Opsonization

• Complement mediated lysis

• Antibody-dependent CMI

Immune response

APC

Immunogen

T

B

PC

Humoral

CMI

T cell – B cell interaction

• Direct– CD 40 on B cells & CD40 ligand on T cells

• Indirect– IL-4 facilitates class switching– INF- inhibits class switching

Primary and secondary antibody response

IgM

IgG

10 20 30 40 50

AbTitre

Days

Maternal IgG in foetus and neonate

2 4 6 8

Birth

8Time(months)

AbTitre

Activators of complement cascade

• Classical– Antigen – antibody complexes

• IgM

• IgG1, IgG2, Ig3

• CRP

• Endotoxin

• Alternate – Microbial polysaccharides such as endotoxin– IgA

Classical Alternate

C3 Convertase(C4b2a)

C3 Convertase(C3bBbP)

C3 ConversionMembrane Attack Pathway

Membrane Attack Complex(C5-9)

Pathways of Complement Activation

Complement Cascade

Classical AlternateC1

C2C4

C3

C5-C9

Ag+Ab Endotoxin

Inhibitors of Complement Cascade

• Classical– C1 esterase inhibitor

– Factor I

• Alternate – Factor I

– Factor H

Biological Properties of the Complement cascade

• Membrane Attack Complex– C5-C9

• Opsonization– C3b

• Anaphylotoxin & chemotaxin– C3a & C5a

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

Acute Phase Proteins

• Either increase or reduction of these proteins occur as a result of the acute phase response (eg; infection, trauma, burn etc.)

• Increase– CRP, Serum amyloid A, Haptoglobin,

Fibrinogen, C3

• 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

Interferons• Type I

– 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

• Influence the nature of the immune response– Th 1 or Th 2 response

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

Major biological activities of INF-

• 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

Cytokine effects on Th1 and Th2 immune response

Enhance Inhibit

Tho

IL-12INF-

IL-4IL-10

IL-4IL-10

IL-12INF-

Th1

Th2

Cytokine effects on Th1 and Th2 immune response

Cytokines produced Effect

Th1 INF-IL-2

Help for CTL and IgGantibody response

Th2 IL-4 IL-5IL-6 IL-10IL-13

Help for IgAand IgE antibody response

Cytokines in the clinic• Cytokine treatment

– enhance immune system• IL-2, INF & INF

– Rx of certain tumours

– enhance haemopoesis• G-CSF

– Rx of low PMN counts resulting from chaemotherapy or irradiation

Cytokines for treatment

• INF- --> some infections• INF- --> Rx of Pts with CGD• G-CSF --> Rx of low granulocyte

count• IL-2 --> Renal cell carcinoma• INF- --> Hairy cell leukaemia

Cytokines in the clinic

• Cytokine receptor targeting– blocking of pro-inflammatory

cytokine receptors• Eg TNF- and IL-1

– TNF- receptor blockers in Rheumatoid Arthritis

Immune response

Protective Damage to host tissues

Hypersensitivity

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

Present classification of hypersensitivity

Gell & Coombs classification of hypersensitivity

+Type V Antibody mediated

(stimulatory)

Time of appearance

Type I 2 to 30 minutes

(immediate)

Type II

(Cytotoxic)

5 to 8 hours

(Intermediate)

Type III

(Immune complex)

2 to 8 hours

(Intermediate)

Type IV 24 – 72 hours

(delayed)

IgE mediated Type 1 hypersensitivity: Allergy

• Commonest type of hypersenisivity

• Range from mild to fatal (anaphylaxis)

• Some individuals (atopic) have a genetic predisposition to make high levels of IgE

• Allergy affects 17% of the population

• Allergic reaction can occur to normally, harmless antigens (such as pollen or foodstuffs) and microbial antigens (fungi or worms

Mechanism of type 1 hypersensitivity

Degranulate:Histamine

Products of cell membrane lipids:Leukotrienes

Cytokines

Mast cell

IgE

Allergen

Preformedmetabolites - histamine

Products of membrane lipids - Leukotrines - ProstaglandinsIL-5

Eosinophil

IL-4B cell

Clinical examples of type 1 hypersensitivity

• Rhinitis

• Anaphylaxis

• Bronchial asthma

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

Clinical examples of type II hypersensitivity

• Rhesus incompatibility– IgG against RhD antigen

• Transfusion reactions– Isohaemaglutinins against major blood group antigens

(A & B)

• Autoantigens– Basement membranes of lung & kidney -

Goodpasture’s syndrome

– Acetylcholine receptor – Myasthenia gravis

– Erythrocytes – Haemolytic anaemia

• Drugs• Stimulatory hypersensitivity

Type III hypersensitivity• Immune-complex mediated • IgG against non-self or self antigens

– Eg; microbes, drugs including antisera & autoantigens (eg; SLE)

• Activation of complement cascade• Local damage: Arthus reaction

– Inhalation of bacterial spores – Farmer’s lung– Avian serum/faecal proteins – Bird fancier’s

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

Clinical examples for type IV hypersensitivity

• Contact dermatitis with– Small molecular weight chemicals

• Eg: Nickel

– Molecules from some plants• Eg; poison ivy

• Post primary tuberculosis

• Tuberculin test (Mantoux test)

Autoimmunity

• Mechanisms of development

• Factors contributing to the development of autoimmune disease

• The spectrum and prevalence of autoimmunity

• Principles of treatment

Autoimmunity is acquired immune reactivity to self antigens. Autoimmune diseases occur whenautoimmune responses lead to tissue damage.

1% - 2% of individuals suffer from Autoimmune diseases.

Immunologic Tolerance

• The unresponsiveness of the immune system to self-antigen.

• Autoimmunity results from failure of mechanisms responsible for immunologic tolerance.

Mechanisms of the development of autoimmunity

• A defect in the mechanisms underlying self-tolerance– Molecular mimicry

• Eg; a cross-reactive antigen between heart muscle and Group A Streptococci predisposes to the development of rheumatic fever

– Modification of cell surface by microbes and drugs (hapten-like manner)

• Drug-induced autoimmune haemolytic anaemia• Thrombocytopenia following viral infections

– Presence of self reactive T cell in peripheral blood

• Extrathymic T cell development

Mechanisms of the development of autoimmunity

• Polyclonal activation via microbial antigens– Eg; endotoxin and EBV

• Availability of normally sequestered self antigens– Eg; lens of eye, central nervous system, thyroid

and testes

• Dysregulation of idiotype network– Eg; antibodies to insulin, TSH and

acetylcholine receptors

Factors contributing to the development of autoimmune

disease• Age

– Higher incidence in aged population• Less stringent immune regulation by the ageing

immune system

• Gender– Women have a greater risk than in men

• Neuroendocrine system influence• Male:Female – SLE 10:1 – Grave’s disease 7:1• Ankylosing spondylitis is almost exclusively a male

disease

Factors contributing to the development of autoimmune

disease• Genetic factors

Disease HLA RiskAnkylosing spondylitis B27 90Reiter’s disease B27 36SLE DR3 15Myasthenia gravis DR3 2.5IDDM DR3/DR4 25Psoriasis DR4 14Multiple sclerosis DR2 5Rheumatoid arthritis DR4 4

Factors contributing to the development of autoimmune

disease• 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

Spectrum of autoimmune conditions

• Organ specific– Addision’s disease - Adrenal cortex– Autoimmune haemolytic anaemia– Grave’s disease - TSH receptors– Guillain-Barre syndrome - Peripheral nerves– Hashimoto’s thyroiditis - Thyroid peroxidase– IDDM - cells in pancrease– PBC - pyruvate dehydrogenase– Pemphigus - epidermal cells– Pernicious anaemia - intrinsic factor– Polymyositis - muscle

Spectrum of autoimmune diseases

• Several organs affected– Goodpasture’s syndrome

• Basement membrane of kidney and lung

– Polyendocrine• Multiple endocrine organs

Spectrum of autoimmune diseases

• Non-organ specific diseases– Ankylosing spondylitis - vertebral– Chronic active hepatitis - DNA– Rheumatoid arthritis - IgG

(Rheumatoid factor)

– Scleroderma - nuclei & centromeres– SLE - dsDNA– Wegerner’s granulomatosis – Cytoplasm of the

neutrophils– PAN - Cytoplasm of the neutrophils

Autoimmune response

Humoral factors Cellular factors

Antibodies Immune complexes

Vasculitis Guillan-Barre syndrome

DermatomyositisHashimoto’s ThyroiditisIDDM

Principles of treatment• Metabolic control

– Graves disease– Pernicious anaemia

• Immune modulators– NSAID– SAID– Immunosuppressive cytotoxic drugs

• Removal of offending antibodies or immune complexes - plasmapheresis

• Surgical– Thymectomy & Splenectomy

Immunology of Transplantation

• Immune Response to graft cells

• Immunology of graft dysfunction

• Strategies to prevent rejection

• Treatment of acute rejection

Immune response to graft cells

Recognition

Self from non-self

Transplantation antigens

Histocompatibility ComplexesMajor

MinorBlood group antigens

Immune Response to graft cells

Presentation of Transplantation antigens

APC T cell

T cell

T cell

Immunology of Graft Dysfunction

• Hyperacute rejection (Within minutes)– Unrecognized ABO incompatibility

– Antibodies to HLA class I (positive cross-match)

• Acute (days or weeks)– CTL (CD8) mediated

• Chronic (months or years)– CD4 mediated

Humoral rejection

Antigen antibody Complexes

Activation of Complement cascade

Chemotaxis & Inflammation

Occlusion of capillaries & prevent vascularization

Strategies to Prevent Rejection• Hyperacute/Acute

- ABO compatibility Tissue matching

Immunosuppresive Therapy

• Chronic - Careful tapering of Immunosuppressive Tissue matching

Treatment of acute rejection• Pulse Corticosteroids

– Pulse methylprednisolone 500 to 1000 mg/day 3 to 5 days

• Antilymphocyte globulin– IV ALG for 7 to 10 days

• OKT3– 5 mg IV for 10 to 14 days

Deficiencies of the immune system• The primary indication of

immunodeficiency – Occurrence of repeated or unusual infectionsAlthough a deficiency may compromise several

components of the immune system, in most instances the deficiency is more restricted and results in susceptibility to infection by some but not all microbes.

For example, defects in T cells tend to result in infections with intracellular microbes, whereas those involving other components results in extracellular infections.

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

• Deficiencies in Membrane Attack Complex (MAC) components– Increased susceptibility to infections with

Meningococcus eg; Neisseria

• C1, C2 or C4 deficiency– Immunecomplex diseases (Unable to remove

Ag-Ab complexes)

Intrinsic Phagocytic defects– Stem cell differentiation

• Neutropenia

– Chemoattraction to the site of microbial assault• Lack of adhesion to endothelium for margination

– Leukocyte adhesion deficiency (LAD) due to a lack of expression (through specific gene mutation) of the critical surface adhesion molecule CD18, a Leukocyte Function Assoicated (LFA) molecule.

– Defective phagocytosis• Lack of fusion of phagosome with lysosomes

– Chediak-Higashi syndrome

– Defective intracelluar killing• Defect in gene coding for NADPH oxidase, involved in

oxygen dependent killing within phagolysosome – Chronic Granulomatous Disease

• Failure to activate NADPH oxidase– Defect in INF or IL-12 receptors –> Mycobacterial infections

Extrinsic Phagocytic defects

• resulting from– Deficiency of antibody or complement

• Defective opsonization

– Suppression of phagocytic activity • Eg by Glucocorticoids or autoantibodies

Deficiency of Humoral immunity• Primary antibody deficiency mainly results

from abnormal development of B cell system.

• Others are the result of defective regulation by T cells.

• The overall lack of antibodies mean that the patients suffer from recurrent bacterial infections, predominantly by Pneumococcus, Streptococcus & Haemophilus

B cell deficiencies• Abnormal B cell maturation

– Lack of Stem cells• Severe Combined Immunodeficiency (SCID)

– B cells fail to develop from B cell precursors• Bruton’s agammaglobulinaemia

– B cells do not switch antibody classes from IgM

• Hyper-IgM syndrome

• B cells that do not respond to signals from other cells– Common Variable Immunodeficiency– Transient hypogammaglobulinaemia

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

• Bruton’s Agammaglobulinemia– X-linked inheritance

• Isolated immunoglobulin defects– IgA deficiency is the commonest

Cellular Immunodeficiency• Result in recurrent viral, fungal,

mycobacterial and protozoan infections• Lack of Thymus

– Di George’s syndrome

• Stem cell defect– SCID – 50% have a defect in chain used by

many cytokine receptors including the IL-2 receptors

• Death of developing thymocytes– SCID – 25% have adenosine deaminase

enzyme deficiency or purine nucleoside phosphorylase deficiency: toxicity due to build up of purine metabolites which inhibit DNA synthesis

Cellular Immune deficiencies• DiGeorge’s 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)

• Nezelof’s syndrome– Cellular immunodeficiency with normal or increased

immunoglobulins

Partial Combined Immune Deficiency

• Wiskott-Aldrich Syndrome– X-linked recessive disorder– Characterized by the presence of eczema,

thrombocytopenic purpura, and increased susceptibility to infection.

• Ataxia-Telangiectasia– Autosomal recessive disorder– Ataxia– Telangiectasia– Recurrent sinopulmonary infections

Secondary (acquired) immunodeficiency

• Commonest immunodeficiency

• Contributes a significant proportion to hospital admissions

• Mainly affects the phagocytic and lymphocytic functions

• Results from infection (HIV), malnutrition, aging, cytotoxic therapy etc.

Factors causing secondary immunodeficiency

• Malnutrition - Protein-calory malnutrition and lack of certain dietary elements (eg; Iron, Zinc); world-wide the major predisposing factor for secondary immunodeficiency.

• Tumors – direct effect of tumors on the immune system by effects on immunoregulatory molecules or release of immunosppressive molecules, eg TGF.

• Cytotoxic drugs/irradiation – widely used for tumor therapy, but also kills cells important to immune responses, including stem cells, neutrophil progenitors and rapidly dividing lymphoyctes in primary lymphoid organs.

Factors causing secondary immunodeficiency

• Aging – decreased T and B cell responses and changes in the quality of the response.

• Trauma – increased infections probably related to release of immunosuppressive molecules such as glucocorticoids.

• Diabetes• Immunosuppressive microbes – malaria,

measles and HIV.

Diagnosis and treatment of immunodeficiency

• Family history – Since defective genes can be inherited, an investigation into the family history is especially important in the diagnosis of primary immunodificiencies

• Evaluation of specific immune components• Antibiotics and antibodies – Antibiotic

therapy is the standard treatment for infections. In addition, antibodies from a pool of donors are used for antibody deficiencies

• Bone marrow transplants and gene therapy

Evaluation of the different components of the immune system

• Evaluation of antibody mediated immunity– Serum electrophoresis– Quantitative estimation of immunglobulins

• IgG, IgA and IgM

– Assay for specific antibodies• Agglutination for IgM antibodies to blood group

antigens A and B• Before and after immunization with killed vaccines

– 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)

Evaluation of different components of the immune system

• Evaluation of cell-mediated immunity– DTH skin tests to common antigens – candida,

streptokinase & tuberculin– Determine

• Total lymphocyte count

• T cell number in blood

• T cell subpopulation percentages (eg; CD4 & CD8)

– Evaluate lymphocyte proliferation to lectins (PHA & Con A) and alloantigens (MLR)

– Analyse T – lymphocyte function• Lymphokine production; INF, IL-2

• Cellular cytotoxicity

Evaluation of the different components of the immune system

• Assay for total haemolytic complement– CH50, a functional assay

• Quantitative estimation of individual complement components

• Assay neutrophil chemotaxis using C in patient’s serum as a chemoattractant

Evaluation of the different components of the immune system

• Determine total granulocyte and monocyte count

• Assay for – Chemotaxis – Phagocytosis – using oponized particles– Superoxide generation using nitroblue

tetrazolium (NBT) reduction– Individual enzymes and for cytokines