Session 14: Immunopathology

Session 14: Immunopathology

• Felician Sikujua (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Identify principles of immune diseases.

Explain types of hypersensitivity reactions.

Explain autoimmune diseases.

Explain immunodeficiency diseases.

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Principles of Immune diseases

Principles of Immune diseases

Deficiencies in immune defenses result in an increased susceptibility to infections, which can be life-threatening if the deficits are not corrected.

The immune system is itself capable of causing great harm and is the root cause of some of the most vexing and intractable diseases of the modern world.

Diseases of immunity range from those caused by “too little” to those caused by “too much or inappropriate” immune activity.

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Types of Immunological diseases

Types of Immunological diseases

Hypersensitivity reactions.

Autoimmune diseases.

Immunodeficiency diseases.

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Hypersensitivity reactions(Immunologic tissue injury)

Hypersensitivity reactions(Immunologic tissue injury)

Hypersensitivity is defined as an exaggerated or inappropriate state of normal immune response with onset of adverse effects on the body.

This term originated from the idea that persons who mount immune responses against an antigen are “sensitized” to that antigen, so pathologic or excessive reactions represent manifestations of a “hypersensitive” state.

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Causes of Hypersensitivity reactions

Causes of Hypersensitivity reactions

Autoimmunity causing autoimmune diseases.

Reactions against microbes e. g. post-streptococcal glomerulonephritis, TB.

Reactions against environmental antigens e. g. pollen, dust giving allergic reactions.

Cross-reaction of antibodies and/or T cells reactive with a microbe with a host tissue(s) e. g rheumatic heart disease (RHD).

Injured host tissues during the process of eradicating infection e. g. viral hepatitis.

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Types of Hypersensitivity reactions

Types of Hypersensitivity reactions

Immediate (type I) hypersensitivity.

Antibody-mediated (type II) hypersensitivity.

Immune complex–mediated (type III) hypersensitivity.

T cell–mediated (type IV) hypersensitivity.

The first three are antibody mediated while the fourth is T cell mediated.

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Immediate (type I) hypersensitivity

Immediate (type I) hypersensitivity

Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host.

The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy.

Many allergens are environmental substances that are harmless for most persons on exposure.

Some people apparently inherit genes that make them susceptible to allergies.

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Immediate (type I) hypersensitivity cont…

Immediate (type I) hypersensitivity cont…

This susceptibility is manifested by the propensity of such persons to mount strong CD4+ helper T cells 2 (TH2) responses and, subsequently, to produce IgE antibody against the allergens.

The IgE is central to the activation of the mast cells and release of mediators that are responsible for the clinical and pathologic manifestations of the reaction.

Immediate hypersensitivity may occur as a local reaction that is merely annoying (e.g., seasonal rhinitis, or hay fever), severely debilitating (asthma), or even fatal (anaphylaxis).

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Events in Immediate (type I) hypersensitivity

Events in Immediate (type I) hypersensitivity

Induced by environmental antigens (allergens) that stimulate strong CD4+ helper T cells 2 (TH2) responses and IgE production in genetically susceptible individuals

IgE coats mast cells by binding to Fcε receptors.

Formation of IgE-mast complex signify sensitisation takes place.

During the second contact with the same antigen (reexposure to the same allergen) leads to cross-linking of the IgE and FcεRI, activation of mast cells, and release of mediators.

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Events in Immediate (type I) hypersensitivity cont…

Events in Immediate (type I) hypersensitivity cont…

Principal mediators are histamine, proteases, and other granule contents; prostaglandins and leukotrienes; and cytokines.

Mediators are responsible for

Immediate phase reactions: vascular reactions (vasodilation, vascular leakage) and smooth muscle spasm.

Late-phase reaction: inflammation and tissue damage.

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Examples of Immediate (type I) hypersensitivity diseases

Examples of Immediate (type I) hypersensitivity diseases

Bronchial asthma.

Allergic rhinitis.

Atopic/Allergic dermatitis (Eczema).

Hay fever.

Hives (Urticaria).

Food allergies.

Anaphylaxis (Severe form of Type I hypersensitivity reaction).

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Antibody-mediated (type II) hypersensitivity

Antibody-mediated (type II) hypersensitivity

It is also called Cytotoxic Hypersensitivity.

But can be non cytotoxic

This type of hypersensitivity is tissue specific.

Most often on blood cells.

Antibodies involved are IgM and IgG.

Those antibodies bind to antigens found on the surface of self cells or tissues.

Reactions by humoral antibodies that attack cell surface antigens on the specific cells and tissues and cause lysis of target cells.

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Antibody-mediated (type II) hypersensitivity cont…

Antibody-mediated (type II) hypersensitivity cont…

Caused by antibodies that bind to fixed tissue or cell surface antigens, promoting phagocytosis and destruction of the coated cells or triggering pathologic inflammation in tissues.

Antibodies against cell or matrix antigens cause diseases that are specific to the tissues where those antigens are present and are usually not systemic.

In most cases, these antibodies are autoantibodies, but they may be produced against a foreign antigen that is cross-reactive with self components of tissues.

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Antibody-mediated (type II) hypersensitivity cont…

Antibody-mediated (type II) hypersensitivity cont…

These antibodies can cause tissue damage by three (3) main mechanisms

Complement-dependent cytotoxic reaction.

The antibodies may opsonize cells or activate the complement system causing direct cell lysis.

Antibody dependent cell – mediated cytotoxicity.

The antibodies may recruit neutrophils and macrophages that cause tissue damage.

Antibody-mediated cellular dysfunction.

The antibodies may bind to normal cellular receptors and interfere with their function.

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Examples of Antibody-mediated (type II) hypersensitivity diseases

Examples of Antibody-mediated (type II) hypersensitivity diseases

Cytotoxic

Goodpasture syndrome.

Autoimmune haemolytic anaemia.

Autoimmune thrombocytopenic purpura.

Pemphigus vulgaris.

Erythroblastosis fetalis.

Graft rejection reaction.

Non cytotoxic

Myasthenia gravis.

Graves disease.

Pernicious anaemia.

Type 2 Diabetes mellitus (Insulin-resistant diabetes mellitus).

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Immune complex–mediated (type III) hypersensitivity

Immune complex–mediated (type III) hypersensitivity

Type III reactions result from deposition of antigen-antibody complexes on tissues, which is followed by activation of the complement system and inflammatory reaction, resulting in cell injury.

Immune complex–mediated (type III) hypersensitivity disorders are caused by antibodies binding to antigens to form complexes that circulate and deposit on tissues and stimulate inflammation.

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Immune complex–mediated (type III) hypersensitivity cont…

Immune complex–mediated (type III) hypersensitivity cont…

The pathogenesis of type III hypersensitivity can be divided into three phases

Formation of antigen– antibody complexes in the circulation.

Deposition of the immune complexes in various tissues.

An inflammatory reaction in various sites throughout the body.

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Examples of Immune complex–mediated (type III) hypersensitivity diseases

Examples of Immune complex–mediated (type III) hypersensitivity diseases

Post streptococcal glomerulonephritis.

Rheumatic fever.

Systemic lupus erythematosus.

Acute serum sickness.

Arthus reaction.

Polyarteritis nodosa.

Drug induced vasculitis.

Reactive arthritis.

Rheumatoid arthritis.

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Type IV (delayed) hypersensitivity

Type IV (delayed) hypersensitivity

Type IV or delayed hypersensitivity reaction is tissue injury by cell mediated immune response without formation of antibodies (contrary to type I, II and III).

A slow and prolonged response of specifically-sensitised T lymphocytes.

T cells may be autoreactive or specific against foreign protein antigens bound to tissues.

T-cell-mediated tissue injury is common during the protective immune response against persistent intracellular microbes.

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Mechanisms of Type IV (delayed) hypersensitivity

Mechanisms of Type IV (delayed) hypersensitivity

Cytokine-mediated inflammation

CD4+ T cells are activated by exposure to a protein antigen and differentiate into TH1 and TH17 effector cells.

Subsequent exposure to the antigen results in the secretion of cytokines.

IFN-γ activates macrophages to produce substances that cause tissue damage and promote fibrosis, and IL-17 and other cytokines recruit leukocytes, thus promoting inflammation.

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Mechanisms of Type IV (delayed) hypersensitivity cont…

Mechanisms of Type IV (delayed) hypersensitivity cont…

T cell–mediated cytotoxicity

CD8+ CTLs specific for an antigen recognize cells expressing the target antigen and kill these cells causing tissue damage.

CD8+ T cells also secrete IFN-γ.

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Examples of Type IV (delayed) hypersensitivity diseases

Examples of Type IV (delayed) hypersensitivity diseases

Tuberculin reaction by PPD.

Contact dermatitis e.g. by poison ivy, jewelries, latex etc.

Viral hepatitis.

Multiple sclerosis (MS).

Guillain-Barré syndrome.

Inflammatory bowel disease (IBD) [especially Crohn's disease]

Peripheral neuropathy

Type 1 diabetes mellitus.

Hashimoto thyroiditis.

Rheumatoid arthritis.

Graft rejection reaction

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Autoimmune diseases

Autoimmune diseases

An immune response has been generated against self-antigens /autoantigens.

There is failure of the immune system to differentiate between self and non-self antigens.

Thus autoimmunity is a state in which the body’s immune system fails to distinguish between self and non self by formation of auto antibodies against one’s own tissues.

Autoimmune diseases are disorders in which the body's immune system reacts against its own tissue and produces antibodies to attack itself.

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Autoimmune diseases cont…

Autoimmune diseases cont…

The presence of circulating autoantibodies does not necessarily indicate the presence of autoimmune disease.

Thus, pathologic autoimmunity is characterized by the autoimmune response is not secondary to tissue injury but it has primary pathologic significance absence of other well-defined cause of disease.

Autoimmunity is loss of immunologic tolerance to one’s own tissue.

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Autoimmune diseases cont…

Autoimmune diseases cont…

Immunologic tolerance is a state in which an individual is incapable of developing an immune response to specific antigens.

It is believed that the breakdown of self-tolerance and development of autoimmunity result from a combination of:

Inherited susceptibility genes, which influence lymphocyte tolerance and

Environmental factors, such as infections or tissue injury, that alter the display of self antigens

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Causes/mechanisms of autoimmunity

Causes/mechanisms of autoimmunity

Immunological factors.

Failure of immunological mechanisms of tolerance initiates autoimmunity

Genetic factors.

There is evidence in support of genetic factors in the pathogenesis of autoimmunity. i.e. familial incidences.

Microbial factors.

Infection with microorganisms, particularly viruses (e.g. EBV infection), and less often bacteria (e.g. Streptococci, Klebsiella) and mycoplasma, has been implicated in the pathogenesis of autoimmune diseases.

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Types of autoimmune diseases

Types of autoimmune diseases

Organ specific autoimmune diseases.

Autoantibodies formed react specifically against an organ or target tissue component and cause its chronic inflammatory destruction.

The tissues affected are endocrine glands (e.g. thyroid, pancreatic islets of Langerhans, adrenal cortex), alimentary tract, blood cells and various other tissues and organs.

Organ non-specific (Systemic) autoimmune diseases.

These are diseases in which a number of autoantibodies are formed which react with antigens in many tissues and thus cause systemic lesions.

Examples: Various systemic collagen diseases.

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Organ specific (localised) autoimmune diseases

Organ specific (localised) autoimmune diseases

Graves disease.

Primary myxedema.

Hashimoto thyroiditis.

Addison diseases.

Type 1 diabetes mellitus.

Crohn disease.

Goodpasture syndrome.

Multiple sclerosis.

Myasthenia gravis.

Autoimmune hemolytic anemia.

Autoimmune thrombocytopenia.

Autoimmune atrophic gastritis of pernicious anemia.

Autoimmune (chronic active) hepatitis.

Primary biliary cirrhosis.

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Organ non specific (systemic) autoimmune diseases

Organ non specific (systemic) autoimmune diseases

Systemic lupus erythematosus.

Rheumatoid arthritis.

Systemic sclerosis (scleroderma).

Sjögren syndrome.

Polyarteritis nodosa.

Reiter’s syndrome.

Wegener’s granulomatosis.

Inflammatory myopathies (Dermatomyositis, Polymyositis).

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Immunodeficiency diseases

Immunodeficiency diseases

The term immunodeficiency covers a group of disorders of specific immune responses that lead to impaired resistance to microbial infections.

Clinically, patients with immune deficiency present with increased susceptibility to infections as well as to certain forms of cancer.

The type of infections in a given patient depends largely on the component of the immune system that is affected.

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Classification of Immunodeficiency diseases

Classification of Immunodeficiency diseases

Primary (congenital) immunodeficiency diseases.

Immune deficiency diseases may be caused by inherited defects affecting immune system development.

Secondary (acquired) immunodeficiency diseases.

They may result from secondary effects of other diseases (e.g., infection, malnutrition, aging, autoimmunity, or chemotherapy).

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Primary immunodeficiency

Primary immunodeficiency

Primary immune deficiency states are fortunately rare.

Most primary immune deficiency diseases are genetically determined.

Caused by mutations in genes involved in lymphocyte maturation or function, or in innate immunity.

Most primary immune deficiencies come to attention early in life (between the ages of 6 months and 2 years), usually because the affected infants are susceptible to recurrent infections.

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Secondary immunodeficiency

Secondary immunodeficiency

Causes of Secondary immunodeficiency.

Infections like HIV/AIDS.

Malnutrition like protein deficiency.

Cancers like Leukemia.

Chemotherapy.

Steroids use.

Renal diseases.

Autoimmunity.

Aging.

Sarcoidosis.

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Key points

Key points

Hypersensitivity reaction refers to an exaggerated immune response that results in tissue injury.

Immediate (type I) hypersensitivity occurs rapidly after interaction of allergen with IgE antibody that is bound to the surface of mast cells in sensitized host.

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue.

Immune complex (Type III) hypersensitivity reaction is induced by antigen-antibody complex that produces tissue damage.

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Key points

Key points

Delayed (Type IV) hypersensitivity is cellular mediated.

Autoimmunity is loss of immunologic tolerance to one’s own tissue.

Primary immunodeficiencies are usually the result of genetic or developmental abnormality of the immune system.

Secondary immune deficiencies may be encountered in patients with malnutrition, infection, cancer, renal disease or sarcoidosis.

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Review questions

Review questions

List five (5) causes of hypersensitivity reactions.

Explain series of events seen in immediate (type I) hypersensitivity.

Explain three (3) mechanisms of antibody mediated (type II) hypersensitivity.

Define autoimmune diseases.

List five (5) causes of secondary immunodeficiency.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 139-162.

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 109-121, 139-143.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 66-78.

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