pathophysiology of immunity prof. j. hanacek, md, phd
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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
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