Immunology for Surgery

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

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, Graves disease 7:1

Genetic factors
Ankylosing spondylitis B27 Reiters 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 virus Shared 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
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

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

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

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 Lchains but not both.

Physical properties of immunoglobulins

Physical IgG properties IgA IgM IgD IgE

Molecular 150 weight kD

170 - 900 420

180

190

Physiological properties of immunoglobulins

Physiological IgG properties Normal adult 8 serum 16 (mg/dl) Half-life in 23 days IgA IgM IgD IgE

1.4 4.0 6

0.4 0.03 ngs 2.0 5 3 <3

Biological properties of immunglobulins

Biological properties
Complementfixing capacity

IgG
+

IgA
_ _ _

IgM
+++ _ _

IgD
_ _ _

IgE
_ +++ _

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 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

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
Immunogen

APC

B
T

PC
CMI Humoral

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

Ab Titre
IgG

IgM 10 20 30 40 50 Days

Maternal IgG in foetus and neonate

Birth Ab Titre

2 4 6 8 Time(months)

Activators of complement cascade

Classical
Antigen antibody complexes
IgM IgG1, IgG2, Ig3 CRP Endotoxin

Alternate
Microbial polysaccharides such as endotoxin IgA

Classical
C3 Convertase (C4b2a)

Alternate
C3 Convertase (C3bBbP)

C3 Conversion Membrane Attack Pathway

Membrane Attack Complex (C5-9)

Pathways of Complement Activation

Complement Cascade Ag+Ab Endotoxin Classical C1 C2 C4 C3 C5-C9 Alternate

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

 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

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

 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

Major biological activities of INF-

Cytokine effects on Th1 and Th2 immune response

Enhance
IL-12 INF- IL-4 IL-10

Inhibit IL-4 IL-10 Th1

IL-12 Th2 INF-

Tho

Cytokine effects on Th1 and Th2 immune response

Th1

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

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 Hypersensitivity Damage to host tissues

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 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)

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

B cell

IL-4
IgE Mast cell Allergen IL-5

Preformed metabolites - histamine

Products of membrane lipids - Leukotrines - Prostaglandins Eosinophil

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 Goodpastures syndrome Acetylcholine receptor Myasthenia gravis Erythrocytes Haemolytic anaemia

Drugs Stimulatory hypersensitivity

 Immune-complex mediated IgG against non-self or self antigens

Activation of complement cascade Local damage: Arthus reaction

Type III hypersensitivity

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

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

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
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

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 selftolerance
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 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

Factors contributing to the development of autoimmune disease

HLA B27 B27 DR3 DR3 DR3/DR4 DR4 DR2 DR4 Risk 90 36 15 2.5 25 14 5 4

 Infections

Factors contributing to the development of autoimmune disease

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
Addisions disease - Adrenal cortex Autoimmune haemolytic anaemia Graves disease - TSH receptors Guillain-Barre syndrome - Peripheral nerves Hashimotos 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
Goodpastures syndrome
Basement membrane of kidney and lung

Polyendocrine
Multiple endocrine organs

Spectrum of autoimmune diseases

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

- 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

Dermatomyositis Hashimotos Thyroiditis IDDM

 Metabolic control

Principles of treatment

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 Complexes Major Minor
Blood group antigens

Immune Response to graft cells

Presentation of Transplantation antigens
T cell

APC

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 infections Although 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)

 Stem cell differentiation

Neutropenia

Intrinsic Phagocytic defects

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

Brutons 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

Brutons Agammaglobulinemia
X-linked inheritance

Isolated immunoglobulin defects

IgA deficiency is the commonest

 Result in recurrent viral, fungal, mycobacterial and protozoan infections Lack of Thymus
Di Georges syndrome

Cellular Immunodeficiency

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

 DiGeorges syndrome

Cellular Immune deficiencies

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

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 patients 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