Diseases of the immune system Prof.dr. Manal Fawzy Gadalla Professor of pathology Faculty of medicine Ain Shams University  

ILOs of the first lecture -Know the types of immune responses and be able to give examples of each type . -What is the pathogenesis of hypersensitivity reactions? -What are the types of hypersensitivity reactions? -What is the pathogenesis of graft rejection? -What are the types of graft rejection?

Immunity refers to a state of protection against infections Mechanisms of normal immune responses: Innate immunity non-specific reaction to a microbe Adaptive immunity specific to the microbial antigen. Humoral immunity: It is mediated by B-lymphocytes Cell mediated immunity: It is mediated by T lymphocytes B cells; that differentiate into plasma cells producing specific antibodies CD4+ helper T cells CD8+ cytotoxic T cells

??? All of the following are considered as innate ways of defense except: A- Complete integrity of the skin B- Mucous released by the respiratory airways. C- IgM against rubella virus D- Hcl content of the stomach

Hypersensitivity Diseases

hypersensitivity diseases Immune responses tissue injury Causes of hypersensitivity diseases: Self antigens autoimmune diseases inflammation Microbes or any injurious agent allergy Environmental antigens

Types of hypersensitivity reactions (according to the immunological mechanisms) Ig E Mast cells Localized bronchial asthma Type 1 Hypersensitivity Generalized anaphylaxis Autoimmune hemolytic anemias Type 2 Hypersensitivity Antibody mediated Localized Arthus reaction Generalized serum sickness Immune complex complement Type 3 Hypersensitivity Cell mediated with T helper cytokines or T cytotoxic TB, Graft rejection Type 4 Hypersensitivity

Hypersensitivity reactions The different mechanisms by which immune system reacts to antigen Type I,II,II Ab mediated Type IV Cell mediated

Type I hepersensitivity Allergic Rhinitis Food Allergies: peanuts, egg, fruits, wheal and flare reaction (atopic urticaria) Asthma: airborne pollens, dust, viral Ag

Mast cell degranulation mediated by antigen cross-linking of IgE bound to IgE Fc receptors (FcRI).

Role of mediators released by mast cells Marked vasodilatation of blood vessels Bronchospasm Increased mucous secretion

Wheal-and-flare reaction (atopic urticaria).

Anaphylaxix: Laryngeal oedema

Type II hepersensitivity reaction (cytolytic hypersensitivity) Antibody binds to the antigen on cell surface leads to cell lysis E.g incompatible blood transfusion

Type III Hypersensitivity reaction immune complex mediated e Type III Hypersensitivity reaction immune complex mediated e.g systemic lupus erythematosis immunecomplex Ag+Ab Deposited in tissue (walls of blood vessels) + complement which activates inflammatory cells

Systemic lupus erythematosus (SLE)

Type IV hypersensitivity reaction delayed (cell mediated) T lymphocytes secrete cytokines lead to macrophage activation which form granulomas e.g TB

??? The pathogenesis of one of the following types of hypersensitivity reactions does not depend on antibodies: A- Type I hypersensitivity B- Type II hypersensitivity C- Type III hypersensitivity D- Type IV hypersensitivity

??? A female patient 30 years old complains of lower lip swelling after eating strwberry, the most propable pathogenesis of her condition is: A- Type I hypersensitivity B- Type II hypersensitivity C- Type III hypersensitivity D- Type IV hypersensitivity

Transplant Rejection

Hypersensitivity reaction types 2 and 4 ( both delayed and cytotoxic) Rejection of transplantation Hypersensitivity reaction types 2 and 4 ( both delayed and cytotoxic) Direct pathway Antigens present on cells of the graft are recognized directly by T helper and T cytotoxic Indirect pathway Antigens present on cells of the graft are presented by APC (antigen presenting cell of the host) T helper (1 and 2) Delayed hypersensitivity Antibody mediated hypersensitivity(BLymphocytes)

Effector mechanisms of graft rejection T cell mediated Rejection AB mediated Rejection T helper (1) Activate macrophages Infammatory cytokines Endothelial cell and parenchymal cell damage Antibodies Complement (C5-9)membrane attack comlpex and leucocytes recruitment Endothelial cell damage T cytotoxic (CD8) Direct toxicity Endothelial and Parenchymal cell damage

Classification of Graft Rejection Hyperacute Antibody mediated endothelial damage Acute vasculitis and ischemic necrosis Acute Cellular and antibody mediated Parenchymal and vascular damage Chronic Cellular mediated Parenchymal and vascular damage

??? One of the following statements is incorrect concerning the graft rejection: A- Chronic rejection occurs within years after transplant. B- Antigen presenting cell is an important component of the direct pathway. C- Hyperacute rejection is merely antibody mediated mechanism. D- The most important target of the transplant rejection is the blood vessels.

ILOs of the second lecture -What is the pathogenesis of autoimmune diseases? -What is systemic lupus erythematosus? -What is the clinical features of SLE? -What are the laboratory investigations of SLE?

Autoimmune Diseases

AUTOIMMUNE DISEASES Immune reaction self antigen disease Organ specific Graves disease Autoimmune hemolytic anemia Systemic Systemic lupus erythromatosus Rheumatoid arthritis Nbn

MECHANISMIS of AUTOIMMUNE DISEASES Autoimmunity loss of self tolerance Infection or injurious agent Genetic Mechanisms of self tolerance Peripheral tolerance Anergy Regulatory T cells Apoptosis Central tolerance T cell thymus B cell bone marrow

SYSTEMIC LUPUS ERYTHROMATOSUS Systemic autoimmune disease female, remission and relapse Any organ affection Autoantibodies direct injury immune complex Break of self tolerance inherited enviromental factors

Pathological features Renal affection Acute necrotizing vasculitis Skin invovement (malar rash) Joint affection CNS involvement splenomegaly Serofibrinous pericarditis and pleurisy Heart involvement

SLE: Malar Rash

SLE: vasculitis

Spleen: Periarteriolar fibrosis (onion skinning)

Clinical manifestation Laboratory investigations Diagnosis Clinical manifestation Laboratory investigations Nnnmn +ve Serum ANA Urine analysis Renal biobsy Serum complement

؟؟؟ A female patient 22 years old presented to ER complaining of severe dyspnea, on examination ,she had pleural effusion. Serum ANA was positive, one of the following statements concerning her case is incorrect: A- There is a defect in her immune tolerance B- She has a decreased level of serum complement C- Malar flush is a renal complication D- She will suffer of multiple excerbations.

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ILOs of the third lecture -Know the types of immune dificiency diseases?. -What is the pathogenesis of AIDS? -What is the Route of infection of AIDS? -What is the clinical picture of AIDS?

Immune Difficiency Diseases

IMMUNE DEFICIENCY DISEASES Causes and types: primary = inherited Secondary = aquired Infection HIV Malnutrition Chemotherapy others Clinical effects: Infection cancers

AQURIED IMMUNODEFECIENCY SYNDROME (AIDS) Retroviral infection (HIV1 ,HIV2) of CD4 positive cells T helper Profound immunosuppression Opportunistic Infections Secondary Neoplasms NEUROLOGICAL MANIFESTATION Opportunistic infection Secondary neoplasms Direct viral affection through macrophages and microglia infection

Routes of infection NO TRANSMISSION BY USUAL PERSONAL CONTACT Sexual transmission Parentral transmission Mother to infant transmission NO TRANSMISSION BY USUAL PERSONAL CONTACT

PATHOGENESIS HIV kill T helper cells

Phases of HIV infection The acute phase: Immunity is intact The chronic phase: Immunity is largely intact The crisis phase: Catastrophic breakdown of the host defenses

Classification of HIV infected patients according to T helper count More than 500 cells/uL: Asymptomatic Between 200 and 500 cells/uL : Early symptoms Less than 200 cells/uL : Severe immunosuppression

Full blown AIDS manifestations Neoplasms Opportunistic Infections CNS Involvement

Opportunistic infections Protozoa and Helminth e.g: toxoplasmosis Fungal infection e.g: candidiasis Bacterial infection e,.g: mycobacteriosis Viral Infection e.g: Herpes Simplex Pneumocystis jiroveci (fungus) Pneumonia

AIDS: pneumocystis carinii infection

AIDS: Oral candidiasis

Neoplasms Kaposi sarcoma Non Hodgkin lymphomas (Burkitt’s, immunoblastic) Primary lymphoma of the brain Cervical carcinoma

CNS involvement Opportunistic infections Neoplasms (primary CNS lymphoma) Aseptic meningitis (viral meningitis) AIDS dementia complex

??? A male 22 years old patient presented to the clinic with high fever, dyspnea, oral thrush, diarrhea, x ray chest revealed complete opacification of the lower right lung lobe, bacteriological examination to the sputum revealed pneumocystis jiroveci: A- What is your diagnosis? B- What is the investigations you would like to do for him? C- What are the expected prognosis of this case?

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ILOs of the fourth lecture -What is amyloidosis? -What is the chemical nature of amyloid protein? -What is the physical nature of amyloid protein? -What are the types of amyloidosis? -What is the gross, microscopic picture of amyloidosis? -What are the investigations of amyloidosis?

Amyloidosis

AMYLOIDOSIS Oid amyl starch Osis process similar Protein (amyloid protein) + mucopolysaccharrhides Interstitial tissues +wall of blood vessels Pressure atrophy May lead to organ failure

Physical nature of amyloid protein

Chemical nature of amyloid protein Amyloid light chain Amyloid associated protein Transthyretin beta2 microglobulin Beta amyloid protein Others

Primary amyloidosis Kidney, liver, spleen Heart, skin, respiratory Multiple myeloma Just increase plasma cells in bone marrow Heart, skin, respiratory Tract, peripheral nerves, tongue Excess kappa and lambda light chains + Defect in enzymatic degradation Kidney, liver, spleen

Secondary amyloidosis Kidney, liver, spleen, LNs, adrenal Tuberculosis, Bronchiectasis, Rheumatoid arthritis Renal cell carcinoma Excess amyloid associated protein+ defect enzymatic degredation

Gross Microscopic Electron microscope non branching fibrils Size enlarged Surface flat Colour brown Consistency Firm waxy Edge sharp Microscopic Homogenous eosinophilic material in Blood vessel wall + interstitial tissue Special stain Congo red +polarized light apple green Electron microscope non branching fibrils

Examples of organs affection Clinical presentation Kidney nephrotic syndrome renal failure Liver Hepatomegaly Spleen sago spleen or diffuse spleen HHeart restrictive cardiomyopathy Others , macroglssia, malabsorption, carpal tunnel syndrome

Generalized amyloidosis poor prognosis Diagnosis of Amyloidosis Clinical symptoms and signs Microscopic Congo red stain Rectal and gingival biopsies Generalized amyloidosis poor prognosis

؟؟؟ A female patient 55 years old with long history of rheumatoid arthritis, complained recently of nephrotic syndrome. Renal biopsy examination revealed mesangial expansion of most of the glomeruli by pink homogenous material, which is present as well in the interstitial tissue: -What is your diagnosis? How can you be sure? -Is it a primary or secondry disease? -Describe other clinical features?

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