Pathophysiology of immunity Prof J Hanacek MD Ph

Pathophysiology of immunity Prof. J. Hanacek, MD, Ph. D

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

Main forms of inappropriate reactions of immune system 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)

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 A) b) hypersensitivity which is harmful B) 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 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 tissues – dermatomyositis – multiple sclerosis – myasthenia gravis – postvaccinal or postinfection encephalitis – polyneuritis – rheumatic fever (heart effects) – cardiomyopathy Gastrointestinal system – celiac disease (gluten-sensitive enteropathy) – ulcerative colitis – Crohn’s disease – atrophic gastritis – primary biliary cirhosis – antibodies against intrinsic factor

Connective tissue – ankylosing spondylitis – rheumatic arthritis – systemic lupus erythematosus – polyarteritis nodosa (necrotising vasculitis) – scleroderma (progressive systemic sclerosis) Eye – Sjögren’s syndrome – uveitis Kidney – immune – complex glomerulonephritis – Goodpasture’s syndrome (basement membrane of glomerulus)

Hematopoietic system – idiopathic neutropenia, lymphopenia – autoimmune haemolytic anemia – autoimmune thrombocytopenic purpura – pernicious anemia Respiratory system – Goodpasture’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: Ig. E – mediated allergic reactions Type II: Tissue specific reactions Type III: Immune-complexes mediated reactions Type IV: Cell-mediated reactions Time corse of hypersensitivity reactions Immediate hypersensitivity reactions – within minutes Delayed hypersensitivity reactions – within sevral hours and days from the time of exposure to antigen

Type I hypersensitivity - Ig. E – 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 - Ig. E – mediated reactions Characteristics: - production of antigen – specific Ig. E after exposure to antigen - the most common alleregic reactions are mediated by Ig. E - antigens which cause allergic reactions are called allergens 3) Atopy Characteristics: - it expresses the proneness to allergy - the atopic persons produce more than normal Ig. E and have more Fc receptors on their mast cells - subtle defect in T-Ly function (e. g. deficiency in Ig. E-specific supressor cells) may account for hightened Ig. E production

Type II hypersensitivity - Tissue specific reactions Characteristics: - destruction of target cells through the action of antibodies against an antigen on the surface of cell membrane 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: - antigen-antibodies complexes (ANt-ATb-C) are created in circulating blood deposition of ANt-Atb-C in the vessel wall or in other extracellular tissues - this reaction is not organ – specific - harmful effect of ANt-Atb-C is caused by activation of complement and by attempt of NE-Le to ingest these complexes releasing of lysosomal enzymes tissue damage

Diseases 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: -it is mediated by specifically sensitised T-Ly - it does not involve antibodies - types of sensitised Ly ivolved in reaction: - cytotoxic T-Ly - lymphokine-producing T-cells Pathologic processes induced by type IV hypersensitivity - graft rejection - tuberculin reaction - tumor rejection - reaction to contact with e. g. metals or ivy

Diseases caused by type IV hypersensitivity • Rheumatoid arthritis - 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: 1) Congenital (primary) immune deficiency - due to genetic disorders 2) Acquired (secondary) immune deficiency - due to another illness-e. g. cancer, viral infection - due to physiologic changes- e. g. ageing - intens stress

Diseases 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 Ig. A, Ig. M, Ig. E 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