Pathophysiology of immunity

Prof. J. Hanacek, MD, PhD

The immune system (IS)

Main physiologic role:

- primary role of IS is to discriminate self from nonself and to eliminate the foreign substance - finely tuned network that protects the host against forein antigens, particularly infection agents

Pathophysiologic changes of immune system:

- the mentioned network can be broken down, causing IS to react inappropriatelly

Hypersensitivity

1) Exaggerated activity against environmental antigens (allergy)

2) Misdirected activity against host’s own cells (autoimmunity)

3) Activity directed against benefitial foreign tissues, e.g. transfusion, transplants (isoimunity)

Hyposensitivity

1) Activity insufficient for protection of the body (immune deficiency)

Main forms of inappropriate reactions of immune system

Types of hypersensitivity

– are differentiated by the sorce of the antigens against which the hypersensitivity is directed

A) Allergy – it has two facets: a) immune response which is benefitial

b) hypersensitivity which is harmful

Definition: Deleterious effects of hypersensitive reactions to environmental (aerogenous) antigens expressed by disease

B) Autoimmunity

– disturbance in the immunologic tolerance of self-

antigens

– immune system reacts agaqinst self – antigens by creating autoantibodies - autoimmune diseases

Autoimmune disease

With main manifestation in:

Endocrine systemEndocrine system – hyperthyroidism (Grave’s disease) – primary myxedema (hypothyroidism) – diabetes mellitus-type 1 – Addison disease – male and female infertility – idiopathic hypoparathyroidism – partial pituitary deficiency

Skin – pemphigus vulgaris – vitiligo – dermatitis herpetiformis

Neuromuscular tissuesNeuromuscular tissues

– dermatomyositis – multiple sclerosis – myasthenia gravis – postvaccinal or postinfection encephalitis – polyneuritis – rheumatic fever (heart effects) – cardiomyopathy

Gastrointestinal systemGastrointestinal system

– celiac disease (gluten-sensitive enteropathy) – ulcerative colitis – Crohn’s disease – atrophic gastritis – primary biliary cirhosis – antibodies against intrinsic factor

Connective tissueConnective tissue

– – ankylosing spondylitisankylosing spondylitis – – rheumatic arthritisrheumatic arthritis – – systemic lupus erythematosussystemic lupus erythematosus – – polyarteritis nodosa (necrotising vasculitis)polyarteritis nodosa (necrotising vasculitis) – – scleroderma (progressive systemic sclerosis)scleroderma (progressive systemic sclerosis)

Eye Eye

– – SjSjöögrengren’’s syndromes syndrome – – uveitisuveitis

KidneyKidney

– – immune – complex glomerulonephritisimmune – complex glomerulonephritis – – GoodpastureGoodpasture’’s syndrome (basement membrane of s syndrome (basement membrane of glomerulus)glomerulus)

Hematopoietic systemHematopoietic system

– – idiopathic neutropenia, lymphopeniaidiopathic neutropenia, lymphopenia – – autoimmune haemolytic anemiaautoimmune haemolytic anemia – – autoimmune thrombocytopenic purpuraautoimmune thrombocytopenic purpura – – pernicious anemiapernicious anemia

Respiratory systemRespiratory system – – GoodpastureGoodpasture’’s disease (interalveolar septas are influenced)s disease (interalveolar septas are influenced)

• Autoantibodies are also produced by healthy individuals,

particularly by the elderly. This is one of the mechanisms

responsible for the ageing process (due to a deterioration

of

tolerance to self-antigens)

• Yonger healthy individuals may produce autoantibodies without the development of overt autoimmune disease (reaction is weak)

Isoimmune disease – immune system of one individual produces an immune reaction

against tissues of another individual, e.g. against transfused Er,

grafted tissue, fetus during its intrauterine life

Pathogenesis of hypersensitivity

– it is not completly understood

Main pathogenetic factors – genetic disorders – infections – another environmental factors- polutants in air, soil, water, psychogenic stressors....

Most diseases related to hypersensitivity evolve because of interaction of at least 3 variables:

a) an original insult which alters immunologic homeostasis

b) the individual’s genetic makeup which determins susceptibility to the effects of the insult

c) immunologic process that amplyfies the insult

Mechanisms involved in development different types of hypersensitivity

Type I: IgE – mediated allergic reactions

Type II: Tissue specific reactions

Type III: Immune-complexes mediated reactions

Type IV: Cell-mediated reactions

Immediate hypersensitivity reactionsImmediate hypersensitivity reactions –– within minutes

Delayed hypersensitivity reactionsDelayed hypersensitivity reactions – within sevral hours and days from the time of exposure to antigen

Time corse of hypersensitivity reactions

Type I hypersensitivity - IgE – mediated

1) Anaphylaxis – rapid and severe reaction developed

within minutes

a) systemic (generalised):

itching, erithema, womiting, abdominal cramps,

diarhea, breathing difficulties, laryngeal edema,

angioedema, vascular collapse, shock, death

b) cutaneous (localised):

signes of local inflammation

2) Allegy - IgE – mediated reactions

Characteristics:Characteristics:

- production of antigen – specific IgE after exposure to

antigen - the most common alleregic reactions are mediated by IgE - antigens which cause allergic reactions are called allergens

3) Atopy

Characteristics:Characteristics:

- it expresses the proneness to allergy

- the atopic persons produce more than normal IgE and have more Fc receptors on their mast cells

- subtle defect in T-Ly function (e.g. deficiency in IgE-specific

supressor cells) may account for hightened IgE production

Type II hypersensitivity - Tissue specific reactions

Characteristics:Characteristics:

- destruction of target cells through the action of antibodies against an antigen on the surface of cell membrane

Explanation:Explanation:

- in addition to HLA system most tissue have tissue specific antigens (TSA) = expressed only on the plasma membrane of certain type of cells

- because of limited distribution of TSA, type II disease are limited to those tissue and organs that expresse the particular antigen

Mechanisms involved in cells destruction in type II hypersensitivity

1) – Antibody (Atb) is bind to TSA

– Atb „fixes“ complement initiation of complement cascade (CCD) lysis of the cell

- e.g. autoimmune hemolytic anemia, transfusion reaction to donor blood cells

2) – Atb is bind to TSA

– macrophages are able to recognize and bind the

opsonised cells phagocytosis lysis of cells

3) – Atb is bind to TSA

– Fc receptors on cytotoxic cells are able to recognize the antigen on the target cells binding of cytotoxic cells on target cells cytotoxic cells release of toxic

substances lysis of target cells

4) – Atb is bind to TSA

– Atb occupy and alters receptors on target cells blockade

of normal ligands for these receptors changes in cellular

functions

- e.g. Grave’s disease

Type III hypersensitivity

Characteristics:Characteristics:

- antigen-antibodies complexes (antigen-antibodies complexes (ANt-ATb-CANt-ATb-C) are created) are created

in circulating blood in circulating blood deposition of deposition of ANt-Atb-C ANt-Atb-C in the vessel wall in the vessel wall

or in other extracellular tissuesor in other extracellular tissues

- this reaction is not organ – specificthis reaction is not organ – specific

- harmful effect of harmful effect of ANt-Atb-C ANt-Atb-C is caused by activation of is caused by activation of

complement and by attempt of NE-Le to ingest these complement and by attempt of NE-Le to ingest these

complexes complexes releasing of lysosomal enzymes releasing of lysosomal enzymes tissue damage tissue damage

Diseases caused by type III hypersensitivityDiseases caused by type III hypersensitivity

• Serum sickness (called according the foreign serum used and symptoms and signs development) - general deposition of immune-complexes in blood vessels,

joints, kydney

- symptoms and signs: fever, enlarged lymphonodes, rash, pain

• Rayanaud’s phenomenon: - temperature-dependent deposition of immune complexes

in peripheral vessel (cryoglobulins)

• Arthus phenomenon: - example of localised immune-complexes-mediated inflammatory

response. It developes due to repeated local exposure to exogenous antigen which reacts with preformed antibodies

in the vessel wall

Type IV hypersensitivity Characteristics:Characteristics:

-it is mediated by specifically sensitised T-Lyit is mediated by specifically sensitised T-Ly

- it does not involve antibodiesit does not involve antibodies

- types of sensitised Ly ivolved in reaction:types of sensitised Ly ivolved in reaction:

- cytotoxic T-Ly- cytotoxic T-Ly

- lymphokine-producing T-cells- lymphokine-producing T-cells

Pathologic processes induced Pathologic processes induced by type IV hypersensitivityby type IV hypersensitivity

- graft rejection - tumor rejection - graft rejection - tumor rejection

- - tuberculin reaction - reaction to tuberculin reaction - reaction to contact withcontact with

e.g. metals or ivye.g. metals or ivy

Diseases caused by type IV Diseases caused by type IV hypersensitivityhypersensitivity

•• Rheumatoid arthritis Rheumatoid arthritis - antigen- antigen is type II collagen in joint tissue

• Hashimoto’s disease - antigen is protein present in thyroid cells

• Diabetes mellitus-type 1- antigen is a protein of the -cells of Langerhans islets

Pathogenesis of hyposensitivity

This disorder results from deficiciences in immunity and leads to

development of different clinical manifestations. The manifestations

are the result of impaired function of one or more components

of the immune system – e.g. B-cells,T-cells, phagocytic cells,

complement

Classification:Classification:

1) Congenital (primary) immune deficiency1) Congenital (primary) immune deficiency

- due to genetic disorders- due to genetic disorders

2) Acquired (secondary) immune deficiency2) Acquired (secondary) immune deficiency

- due to another illness-e.g. cancer, viral infection- due to another illness-e.g. cancer, viral infection

- due to physiologic changes-- due to physiologic changes- e.g. ageinge.g. ageing

- intens stress- intens stress

Diseases caused by immune deficiencyDiseases caused by immune deficiency

• Primary T-cell defects

- severe combined immune deficiency (SCID)

- Di George syndrome (thymic aplasia or hypoplasia)

• Primary B-cells defects

- agammaglobulinemia

- selective IgA, IgM, IgE deficiencies

• Phagocytic defects

a) quantitative defects -e.g. congenital splenic aplasia,

Sickle cell anemia, congenital neutropenia

b) chemotactic defects – lazy leucocyte sy.

c) microbicidal defect – chronic granulomatous disease – myeloperoxidase deficiency

• Complement defects