1. Disorders of Immunity

2. Immunity is a defense mechanism of the body and is a collection of cells and molecules.
Immune system protect against exogenous substances, microbial invasion and possibly tumors.
Occasionally immune response also damage normal host tissue and react to homologous antigens (e.g; blood transfusion, transplanted tissue, fetal antigen in pregnancy) and some times endogenous. antigens.

3. Immune types : consist of two broad categories.
Innate immunity (natural or native immunity):
Mediated by cells and proteins that are present even before infection and includes physical barriers (skin, saliva, PH, cilia and complement system); phagocytic cells (neutrophils and macrophages) and natural killer (NK).
It is the first line of defense because it is always ready to prevent and eradicate infection.
Two most important cellular reaction are inflammation and anti- viral defense.

4. 2. Adaptive immunity (acquired or specific immunity):
Consist of mechanisms that are stimulated by microbes and are capable of recognizing microbial and non- microbial substances.
More powerful than innate immunity in combating infection.
It consist of lymphocytes and their products.
Classified into two categories :

5. A-humoral immunity.
Protect against extracellular microbes and their toxins that mediated by B-lymphocytes and their secreted products antibodies.
B- cell mediated (cellular) immunity.
Responsible for defense against intracellular microbes that mediated by T-lymphocytes

6. Immune response Hypersensitivity. Autoimmune disease.
Immune deficiency.
Tissue transplantation rejection.
Amyloidosis.

7. Hypersensitivity. It is excessive response to antigen. Types
Type I hypersensitivity: immediate hypersensitivity (anaphylactic reaction).
Type II hypersensitivity: Antibody mediated cytotoxicity.
Type III hypersensitivity: immune complex reaction (Ag-Ab reaction).
Type IV hypersensitivity: cellular mediated immune reaction (delayed)

8. Cells of immune system
Lymphocytes: which are mediator of adaptive immunity classified into T and B- lymphocytes.
Antigen presenting cells (APCs) that capture and display antigen-includes dendritic cells and macrophages.
Other effector cells as leukocytes, NK and plasma cells.

9. Mechanisms of immune mediated injury.
Type I Hypersensitivity (Anaphylactic).
Rapid immunological reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen.
Mediated by IgE antibodies formed in response to a particular antigen (allergen) and bound to mast cells and basophils.
Synthesis of IgE antibody is highly dependent on the induction of CD4+ helper T-cells of the TH2.
IL-4 produced by TH2 is essential for IgE synthesis

10. Two phases may be exhibited :
The initial rapid response-become evident in 5-30 min after re-exposure with resolution within 30 min-induced by primary mast cells mediators.
Second delay phase-sets in 2-8 hrs. later and last for days and characterized by intense infiltration by inflammatory cells and tissue damage.
Clinical examples-bronchial asthma, infantile eczema, food and drug allergy and anaphylactic shock

11. Systemic anaphylaxis
Follow parenteral or oral administration of allergens, such as antisera, drugs and hormones.
severity reflect level of sensitization and even minuscule dose may induce shock in the appropriate host.
Pruritis, urticarial and erythema occur minutes after exposure , followed by bronchoconstriction and laryngeal edema, shock and death within minutes to hours.

12. Local anaphylaxis (atopic allergens).
Atopy is a hereditary predisposition to develop local Type I response to inhaled or ingested allergens.
It affect 10% of the population and include urticaria, angioedema, rhinitis and asthma.

13. Type II hypersensitivity: Antibody mediated cytotoxicity.
Caused by antibodies that react with antigen present on cell surface or in extracellular matrix.
The antigenic determinants may be intrinsic to the cell membrane or matrix or they may take the form of an exogenous antigen such as drug metabolites that is adsorbed on cell surface or matrix.
The target cells are RBC , WBCs and platelets, also the extravascular elements involve such as basement membrane and receptors.
This type mediated by IgM, IgG, and IgA

14. Clinical examples:
Autoimmune hemolytic anemia.
Auto immune thrombocytopenia purpura.
Acute rheumatic fever.
Myasthenia gravis.

15. Type III hypersensitivity: immune complex reaction (Ag-Ab reaction).
Mediated by Ag-Ab complex-immune complex- forming either in the circulation or at extravascular sites of antigen deposition.
Antigen may be exogenous ( infectious agents) or endogenous.
Systemic immune complex- as acute serum sickness and chronic serum sickness.
Local immune complex as vasculitis and renal glomeruli.

16. Type IV hypersensitivity: cellular mediated immune reaction (delayed)
Initiated by specifically sensitized T-lymphocytes and includes delay type hypersensitivity and T-cell mediated cytotoxicity.
delay type hypersensitivity is principle pattern in response to mycobacterium tuberculosis, fungi, protozoa and parasites, also in graft rejection.
T-cell mediated cytotoxicity-generation of CD8+ cytotoxic T- lymphocytes and principle pattern of response to viral infection and to tumor cells and also to graft rejection.

17. Autoimmunity: Are the immune reactions against self-antigens and an important cause of certain diseases in humans. Autoimmune diseases are the result of damage to the body by the presence of autoantibodies or autoreactive cells About 2% of the population are affected by such diseases. Examples of Autoimmune Diseases Two major categories - Systemic autoimmune diseases - Single-organ autoimmune diseases

18. Autoimmune hemolytic anemia Myasthenia gravis Hashimoto’s thyroiditis
Organ specific autoimmune diseases:
Autoimmune hemolytic anemia
Myasthenia gravis
Hashimoto’s thyroiditis
Type 1 diabetes mellitus
Multiple sclerosis

19. Systemic autoimmune disease: - Systemic lupus erythamatous (SLE)
Systemic autoimmune disease: Systemic lupus erythamatous (SLE) Rheumatoid arthritis Systemic sclerosis

20. MECHANISMS OF BREAKING OF SELF-TOLERANCE
Immunological tolerance is the phenomenon of unresponsiveness to an antigen as a result of exposure of lymphocytes to that antigen.
The mechanisms of self-tolerance can be broadly classified into two groups:
central tolerance
peripheral tolerance.

21. Several mechanisms that contribute to delete autoreactive T and B cells in peripheral tissues. - Anergy: Functional inactivation of lymphocytes. - Suppression by regulatory T cells: This type of cell plays a major role in preventing immune reactions against self-antigens. - Deletion by activation-induced cell death: CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis.

22. Hashimoto’s Thyroiditis Hashimoto’s thyroiditis is organ specific autoimmune disease that interfere with the thyroid gland function - The thyroid gland located in the anterior region of the neck consist of units called follicles. - Follicles are lined with cuboidal epithelial cells and filled with colloid -The primary constituent of colloid is thyroglobulin which is made up of triiodothyronine (T3) thyroxine (T4)

23. This is the normal appearance of the thyroid gland on the anterior trachea of the neck. The thyroid gland has a right lobe and a left lobe connected by a narrow isthmus. The normal weight of the thyroid is 10 to 30 grams.

24. This symmetrically small thyroid gland demonstrates atrophy
This symmetrically small thyroid gland demonstrates atrophy. This patient was hypothyroid. This is the end result of Hashimoto's thyroiditis. Initially, the thyroid is enlarged and there may be transient hyperthyroidism, followed by a euthyroid state and then hypothyroidism with eventual atrophy years later. Hashimoto's thyroiditis results from abnormal T cell activation and subsequent B cell stimulation to secrete a variety of autoantibodies.

25. This high power microscopic view of the thyroid with Hashimoto's thyroiditis demonstrates the pink Hürthle cells at the center and right. The lymphoid follicle is at the left. Hashimoto's thyroiditis initially leads to painless enlargement of the thyroid, followed by atrophy years later.

26. Systemic Lupus Erythematosus - It is a chronic systemic inflammatory disease marked by alternating exacerbation and remissions - Approximately 1 in every 2000 individuals are affected - Age of onset is usually between 20 and 40 yrs of age - Women are more affected than men - Etiology is unknown but may be due to genetic and environmental factors In whites, it is strongly associated to with HLA-DR3 or DR The SLE cell is a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil

27. Clinical Signs: - A skin manifestation of an erythematous rash may appear in the area of body exposed to UV light - A classic butterfly rash across the nose and cheeks Some patients may also exhibit renal involvement

28. - Renal involvement is usually in the form of lesions the most dangerous of which is glomerulonephritis - Immune complexes may deposit in the subendothelial tissue and thickening of the basement membrane results - All of these can result in renal failure and death
Glomerulonephritis
Normal

29. Tissue Transplantation Rejection is the process of rejection against transplant tissue Types of tissue transplantation ((graft)) Allograft :- Transplantation of organ from one individual to another of the same species ( person-person). Ex Liver, kidney Autograft :- Occur in the same individual. Ex. skin transplant Zoonograft :- Transplantation of organ from one individual to another of different species.

30. There are two main mechanisms by which the host immune system recognitions and respond Major histocmbatibility molecules (MHC) on the graft. Direct recognition and Indirect recognition

31. Recognition and rejection of organ allografts
Recognition and rejection of organ allografts. In the direct pathway, donor class I and class II MHC antigens on antigen-presenting cells in the graft (along with costimulators, not shown) are recognized by host CD8+ cytotoxic T cells and CD4+ helper T cells, respectively. CD4+ cells proliferate and produce cytokines which induce tissue damage by a local delayed hypersensitivity reaction. CD8+ T cells responding to graft antigens differentiate into CTLs that kill graft cells. In the indirect pathway graft antigens are picked up, processed, and displayed by host APCs and activate CD4+ T cells, which damage the graft by a local delayed hypersensitivity reaction and stimulate B lymphocytes to produce antibodies.

32. On the basis of the morphology and the underlying mechanism, rejection reactions are classified as hyperacute, acute, and chronic Hyperacute Rejection: This form of rejection occurs within minutes or hours after transplantation Immunoglobulin and complement are deposited in the vessel wall, causing endothelial injury. Is mediated by preformed antibodies that recognize HLA antigens in donor organ. Usually these are formed as a consequence of blood transfusion, pregnancy, prior organ transplantation, autoimmune diseases. Fibrinoid necrosis lead to immediate graft loss. Delayed form may occur several days following transplantation.

33. Hyperacute rejection.

34. Acute Rejection: IS mediated by activated T-lymphocytes
Acute Rejection: IS mediated by activated T-lymphocytes. - Activations of T-cells occur after recognition of graft antigen either directly or after being processed and presented by APC. - This usually occur during the first 6 months It manifest as increase in s. creatinine with or without oliguria.

35. Chronic Rejection: Occur after immunosuppressive therapy, and chronic rejection has emerged as an important cause of graft failure.

36. Immunodeficiency diseases Immunodeficiency diseases may be caused by inherited defects affecting immune system development or they may result from secondary effects of other diseases (e.g. infection, malnutrition, aging, immunosuppression, autoimmunity or chemotherapy).

37. Primary immune deficiency: Caused by mutations in genes involved in lymphocyte maturation or function, or in innate immunity. Some example of these disorders are: 1- X-Linked Agammaglobulinemia: Failure of pre-Bcell to differentiate into B-cell; these result absence of gamma globuline in the blood. 2- CommoneVarible immunodeficiency: Characterized by hypogammaglobulinema, impairdAb responses to infections. 3-Selective IgA deficiency: failure of IgA production. 4- Severe Combined immunodeficiency (SCID): failure of T-cell and B-cell maturation. 5- Autosomal SCID: failure of T cell development , secondary defect in Ab responses 6- X-Linked hyper IgM syndrome: failure to produce isotype-switched high-affinity Abs (IgG,IgA,IgE) , mutation in gene encoding CD40L.

38. Secondary immune deficiency: Which may arise as secondary to other diseases or therapies are much more common than the primary. Secondary type may be encountered in patients with cancers, infections, malnutrition, or side effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases. The one example of this type is Acquired Immune Deficiency Syndrome (AIDS).