lecture 12 immunopathology

Prof.Dr.

Khalil Hassan Zenad Aljeboori

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IMMUNOPATHOLOGY

Lecture 12

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Body immune responses are normal defense mechanism designed to protect the body from various environments factors, but the diseases may result from:

1. In adequate immune response.(immunodeficiency)2. In appropriate immune response.(autoimmune diseases ,Graft rejection)3. Excessive immune response (hypersensitivity).4. Amyloidosis.

1) In adequate immune response:Result from immunodeficiency states there are 2 classes of immunodeficiency syndrome:

1. Primary immunodeficiency at birth due to genetic disorders.2. Secondary immunodeficiency during the life (acquired).

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1-Transient hypogammaglobinemia this occur in infants during 3-6 month of birth, in which breakdown of maternal IgG it is considered physiological hypogammaglobinemia, and occur when infants unable to synthesize IgG level so child become susceptible to recurrent pyogenic infection.2-X-linked a gammaglobulinemia (Bruton disease) it is a genetic disorder in which failure of B cells maturation result in absence of antibodies, the disease mostly occur in males so suffering from recurrent bacterial infection.3- Isolated IgA deficiency:There is reduction in IgA level but other antibodies are normal level.4-Hyper IgM syndrome:In normal condition IgM and IgD produced first against protein antigen (Ag), followed by IgG, IgA and IgE antibodies (Ab). Patient with this syndrome have normal level of IgM or abnormal level of IgM Abs but fail to produce other Abs such as IgG, IgA, IgE, although IgM important for the fixation of complement for activation and opsonization bacteria.

Primary immunodeficiency:

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5-IgG subclasses deficiency :Selective of IgG (IgG1, 2, 3, 4) are easily missed because IgG1 contribute 70- of total IgG-IgG2 predispose the individuals to respiratory infections and meningitis. IgG2 deficiency occur together with IgG4 and IgA. Similarly IgG1 and IgG3 are commonly seen deficiency together.6-Thymic hypoplasia (diGoeorge syndrome)Affective T cells due to hypoplasia of thymus glands occur together with hypoplasia of parathyroid gland so hypocalcemia, tetany, cardiac malformation, facial abnormalities.7-Severe combined immunodeficiency:This inherited either autosomal or x-linked occur due to failure of development of B and T cells, therefore thymus is small and body lymphoid tissue are also small so children are susceptible to candida thrush, pneumonia, diarrhea.8- Defects in neutrophils and complement system.

ContinuedPrimary immunodeficiency:

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More common than primary, it occur during life, caused by:

1- Protein loss (nephrotic syndrome).2- Impaired protein synthesis, malnutrition.3- Lymph proliferative disease: lymphoma, leukemia.4- Multiple myeloma.5- Immunosuppressive drugs.6- Spleenectomy, tonsillectomy.7- Infections such as cytomegalovirus. Measles, rubella, infectious mononucleosis, viral hepatitis.

Secondary immunodeficiency :

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It is retrovirus disease caused by human immunodeficiency virus (HIV) characterized by:1- Immunosuppression leading to opportunistic infections.2- Secondary tumors.3- Neurological manifestationsThe diseases is worldwide, about 20 years ago discovered and more than 22 million people died.

Three major routes for the transmission of virus:1- Sexual contact.2- Parenteral inoculation drugs, hemophilia, blood transfusion.3- Infected mother to newborn.Cause: retrovirus belong to lenti virus family (HIV 2types) HIV-1 in USA, Europe, central Africa where HIV-2 in West Africa.

Acquired immunodeficiency syndrome (AIDS)

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Two major targets for HIV immune system and central nervous system:

*In immune system:Aids lead to impair cell mediated immunity. It distruct CD4+ lymphocytes and decrease helper\ suppressor T cells ratio.Virus has selective tropism for CD4+ and macrophages and dendritic cells. Whereas viral envelope bind to other cells to enhance cell entry. The virus core enter the cytoplasm have genes undergoes for reverse transcriptase in which complementary DNA making and enter nucleus of cells as a latent provirus DNA transcribed to from complete virus, bud from the cell membrane and death of the cells.HIV colonizes the spleen, lymph node, tonsils. The T cells, macrophages and dendritic cells represent reservoir of infection.*In central nervous system:Virus carried into brain by infected monocytes in brain microglia (equivalent macrophages) is the target for HIV. In brain the neurological deficit is caused by indirect viral products, cytokines produced by macrophage/ microglia.

Pathogenesis:

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1-Primary infection:At the beginning when viral replication in body organs, an immune response developed with increase virus infected CD8+ to replace dying T cells, followed by decrease CD4+/ CD8+ ratio, resulted in influenza, skin rash, lymphadenopathy.

2-Asymptomatic phase (incubation period):In this phase the immune system is intact but viral replication continued, this stage may still for years, patients have AbS and transmit the disease.

Clinical phases:

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3-Aids related complex:In this CD4+ infected cells increased, their function impaired, their number in blood fall to 400 cell/ UL So malaise, fever, night sweating weight loss, diarrhea and lymphadenopathy. Impaired CMI and CD4+ so fungal infection, salmonella and hemophilus are sever.

4-Aids (crisis phase):In which fully developed immune deficiency so fatigue, fever, weight loss, lymphadenopathy and diarrhea, CD4+ cells is below 400/UL. So most of opportunistic infection, secondary tumors and neurological manifestations occurred and death.

Clinical phases:

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Responsible for 80% of aids patients death it include:1- Pneumocystis carinii pneumonia.2- Recurrent candidiasis.3- Cytomegalovirus infection mainly retinitis, enteritis.4- Herpes simplex infection in mouth, perianal infection.5- Mycobacterium infection.6- Toxoplasmosis.7- Cryptococcus meningitis.8- Cryptosporidium- enteritis.Patients with aids have high incidence of Neoplasms (Tumors): due to defects in T cells so;

1-Kaposi sarcoma occur in association with human herpes virus (KS) infect skin, lung, lymph node, GIT.

2-Non-Hodgkin's lymphoma occur in association with (EBV) Epstein bar virus. It affect brain, lymphoid tissue.

3-Cervix-uterus carcinoma tissue it occur with papilloma virus.

Opportunistic infections:

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2)In appropriate immune response

1. Transplant rejection, organs transplantation used to treat irreversible diseases of kidney, liver, heart, lung and bone marrow. The action of immune system destroy the transplanted tissue by HI and CMI directed against the MHC Ag (HLA) of donor graft endothelial cells are rich with MHC (HLA) Ag and blood group Ag.

Types of transplant rejection:

1-Hyper acute rejection: Occur within minutes to few hours. There is wide spread thrombosis, focal necrosis, it formed due to reaction of preformed Abs against graft Ags. These Abs developed either by:

1. Previous rejection of previous graft.

2. Women who develop anti HLA Abs against paternal Ags.

3. Prior blood transfusion.

2-Acute rejection: Occur within days or weeks, when stop immunosuppressive drugs also occurred by HI and CMI against donor graft Ag. Particularity MHC class II Ag. So renal failure with infiltration of CD4+, CD8+ vasculitis endothelial necrosis, neutrophils infiltration, damage of B.V.

3-Chronic rejection: Occur slowly during months and years of graft transplant. It is slowly breakdown of self-tolerance to graft due to inadequate immune suppression. So increase creatinine level (renal dysfunction). Antimal fibrosis lead to ischemic damage hyalinization, loss of glomeruli, tubular necrosis, atrophy and interstitial fibrosis.

Transplantation of other organ liver, heart, lungs, pancreas unlike of kidney it can preformed with:

1. ABO blood grouping.

2. Absence of preformed Abs.

3. Body habitus example child not receive heart of adult.

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1) Autoimmune diseases:

It resulted from reaction of immune system against self-antigen (Ag) i.e. against body tissue or components. This

immune reaction either by autoantibody or cell mediated immunity. In autoimmune diseases the normal mechanism

of tolerance for self (Ag) were break down. In self-tolerance lack of immune response to body own tissues. Some of

autoimmune diseases have genetic component i.e. some diseases associated with particular HLA histocompatibility

type. In other situation autoimmune diseases triggered by infection such as rheumatic myocarditis cross Ag of

streptococcus with myocardial myosin.

Immunological tolerance:

Both T.B cells bear self-reactive molecules (receptors) recognize cell in tissue, cause damage resulted in autoimmune

disease. To avoid such as incidence both T.B cells bearing such receptor must be either eliminated or down regulated,

so that the immune system become non-reactive (i.e. tolerance to self Ag) this in normal individual. The T cell

tolerance is much more important than B cell tolerance because both types of immunity depend on T cell cooperation.

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Thymic tolerance: achieved through elimination all T cells capable for recognize self Ag.

Peripheral tolerance: involve several mechanism:

1-Immunological ignorance:Self Ag are invisible to immune system either sequestration of Ag in fluid such as vitreous humour of eye or present in low level to CD4+ and Ag processing cells so no immune activation, also slow gradual tissue break down during the apoptosis, so No self Ag.

2-Energy: CD4 T cells require two signals for initiation immune response one signals from Ag specific signals through T cell receptor, the other signals from Ag processing cell such interaction occur in secondary lymphoid organs (L-node) if no 2nd signals (from Ag- presenting cells) unavailable the only stimulation by T cell receptor alone lead to apoptosis.

3-Suppression: self-reactive T cell suppressed by suppressor T cells (CD8+) produced cytokines inhibited CD4+ helper activity.

4-B-cell tolerance: the production of self-reactive Abs by these cells limited by lack T cell help.

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Break down of immunological tolerance( above) lead to auto immune disease through the:

1- Overcoming peripheral tolerance when excess self Ag to presenting cells or alteration of self Ag by viruses, radiation, free radicals or during tissue damage (testis) due to trauma or traumatic uveitis when these Ag kept sequestered in these two organ against immune response.

2- Molecular mimicry:Structured similarity between the self Ag and microbial AgS (example) streptococcus- in systemic infection this cross reactivity between self Ag and microbial Ag enhance T cell immune response against body tissue such as glomerulonephritis, rheumatic myocarditis .

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1- Genetic factors: through the :a- Different autoimmune diseases are present in the same family like LE, autoimmune hemolytic

anemia and autoimmune thyroiditis.b- Subclinical autoimmunity is common in family members. The association between genetic

factor and autoimmunity involve MHC (HLA) genes especially type II Ag with autoimmunity.2- Environmental factors: many factors trigger the autoimmunity:

1- Hormones so most of autoimmune diseases occur in female more than in male and during reproductive years indicate estrogen had, role in autoimmunity, in animal model remove ovary inhibit autoimmune disease, but giving estrogen enhance onset of disease.

2- Infections: also associated with autoimmunity in some parts of world.In animal model supported this association.

3- Drugs: also associated with autoimmune diseases such as in HLA-DR2 is associated with penicillamine- induce myasthenia gravis where as an DR3 penicillamine induced nephritis so genetic variation is important, similarly drug induced SLE.

4- Ultraviolet- act either modify self Ag to become immunogenic or by enhancing apoptosis with release of surface Ag (auto Ag) that hidden in the cell, such exposure of these Ag on surface of cell lead to Ag- Ab reaction and tissue damage.

Etiology of autoimmune diseases:

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1- Organ specific autoimmune diseases:1- Vitiligo- skin- hypopigmentation.2- Graves- disease- thyroid- hyperthyroidism.3- Hashimotos disease- thyroid- hypothyroidism.4- Addison disease- adrenal- hypoadrenalocortism.5- Autoimmune gastritis- stomach- pernicious anemia.6- Type I diabetic mellitus- insulin producing cell (B. cells) - DM.7- Myasthenia gravis- skeletal muscles- muscle fatigue.

2-multiorgan involvement of autoimmune diseases connective tissue disease or collagen vascular diseases.1- Systemic lupus erythematosis- skin, kidney, lung, joint, heart.2- Progressive systemic sclerosis- skin, gut, lung.3- Polymyositis dermatomyositis- skin, skeletal muscles.4- Rheumatoid disease- joints, lungs systemic vessels.

Classification of autoimmune diseases:

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Systemic lupus erythematous:One of connective tissue disease affecting female than male with young ages, it involve multiple organs. It controlled by steroids or immunosuppressive drugs, renal failure, current infections, CNS involvement is the cause of death.

Etiology SLE: a complex disease of multifactorial origin including genetic hormones and environmental factors resulting T-B cells activation and produce several autoantibodies due to main failure or less self-tolerance.Among the autoantibodies antinuclear Abs against nuclear Ag and auto Abs against double stranded DNA both Ab are diagnostic. Auto Abs against blood cells, platelets, lymphocytes, anti-phospholipids Ab (phospholipid important for blood clotting) so Ab against phospholipid are in patients with venous and arterial thrombosis.

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Genetic predisposition for SLE.1-High incidence in monozygotic twin than in dizygotic twin.2-In the family members.3-Positive association of SLE with HLA- II.4-May accompanied with inherited complement deficiency.

Complement remove Ag-Ab complexes so lack of complement impair removal of Ag-Ab complexes so tissue damage.

Non genetic causes:1-Include environmental factors (drugs) most LE like syndrome in patients taking drugs,

procainamide, hydralazine.2-Hormones sex hormones, female more than male affected with LE due to estrogen effect.3-Ultraviolet light- which induce damage DNA and promote cell injury with release cell

component augment the formation of DNA and anti DNA immune complexes.and these immune complexes are detected in glomeruli, also Hb against RBCS, platelets, WBCs. The denatured nucleus of injured cell were engulfed by neutrophils and macrophage and detected easily (LE cells).

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1- Discoid skin rash.2- Malar mash.3- Photosensitivity.4- Oral ulcer.5- Arthritis.6- Serositis.7- Renal disorders.8- Neurologic disorders.9- Hematologic disorders.10-Immunological disorders.11-Presence of antinuclear Abs and anti DNA Abs.

Clinical manifestation:

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Systemic sclerosis ( scleroderma):It affect connective tissue of the different organs in many system, more common in female than male in middle age. The main abnormality excess fibrous tissue on the vessels wall, perivascular fibrosis, lead to progressive ischemic damage in many organs (skin was mostly affected scleroderma), but GIT, lung, kidney heart. In the skin the lesion in finger, upper extremities to upper arm, shoulder, neck, face.

Rheumatoid arthritis (RA)Multisystem connective tissue disease, the dominant effect are on the joints with presence circulating Abs (rheumatoid factor ,RF), common in female than in male, at 35-45 years, middle age) the disease no limited to joint but affect skin, lungs, eye, blood vessels.

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Affect small and large joint of hands and feet.1-rheumatoid synovitis swollen of synovium, mononuclear cells

infiltration(lymph, macrophages and plasma cell) with lymphoid nodules (follicles ) formation hypertrophy, hyperplasia of synovium, vascularity and fibrinous effusion in joint space.

2-Articular cartilage destruction, replaced by granulation tissue (pannus) across the surface of articular cartilage from edge of joint.

3-The inflammatory pannus cause destruction of adjacent bone together with cartilage, the pannus fill joint space subsequent fibrosis, ankylosing of affected joint, finally lead to secondary osteoarthritis especially in joint weight bearing (knee joint). Destruction of tendon, joint capsule, and ligament lead deformities of joints.

Pathological change:

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Firm, oval to round at the surface of forearm up to 2cm diameter composed of fibrinoid necrosis.

Pulmonary involvement of RA lead to interstitial pneumonitis, fibrosing alveolitis called honeycomb lung, also accompanied by anemia.

Pathogenesis of RA:Genetic predisposition in first degree relative and in HLA-DR4 and or HLA- DR1. Patients have rheumatoid factor (RF) is IgM directed against fc region of IgG. RF (IgM) and IgG immune complex fix complement attract neutrophils to area and type III hypersensitivity reaction. CD4 T cells activated give cytokines

1-Activate macrophages to produce proteolytic enzyme that cause inflammation and tissue destruction.

2-Activate B cells produce (RF) autoantibody with IgG cause immune complexes, subsequent joint injury.

3-Activated T cell induce osteoclast lead to bone resorption.

Rheumatoid cutaneous nodules:

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Juvenile rheumatic arthritis:Occur in children like in adult cause destructive arthritis but differ from destructive arthritis by:1- Affect large joints.2- Absence of RF.3- No rheumatoid nodules.4- Occur in association with HLA-B27.

Sjogren syndrome:Characterized by dry eye and mouth (keratoconjunctivitis sicca) and xerostomia) respectively resulted from anti immune destruction of lacrimal, (salivary gland) it occur primary disorder or secondary with other autoimmune diseases such as RA, SLE, polymyositis, thyroiditis, multiple sclerosis and vasculitis.

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Characterized by immune mediated muscle injury and inflammation it present:

1-Polymyositis.2-Dermatomyositis.3-Inclusion body myositis.

It occur alone or with other autoimmune diseases as systemic sclerosis it affect the muscle of trunk, neck, limb and involve skin, eyelid, in case of dermatomyositis, so skin rash, periorbital edema histologically lymphocytes infiltration with muscle degeneration.

Inflammatory myopathy

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It is systemic disease characterized by inflammation and necrosis of wall of arteries.

The clinical effect from vessel occlusion lead to infarction. The most organ affected kidney, GIT, liver, CNS, peripheral nerves, skin, muscles. It is an immune complex mediated, there is association with hepatitis B virus.

Polyarteritis nodosa (PAN)

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1- Hashimoto thyroiditis :Is an autoimmune disease that result in destruction of thyroid gland and gradual thyroid failure and painless thyroid enlargement. There is autoantibodies against thyroglobulin and peroxidase. Hashimoto thyroiditis has a strong genetic component. The autoimmunity effect of this disease:

1-Is depletion of thyroid epith by apoptosis.2- Replace thyroid epith. By mononuclear cells infiltration with germinal centers and fibrosis.3- CD8+ destroy the thyroid follicles.4- CD4+ T cells produce interferon gamma in thyroid tissue resulted in activation of macrophages

and damage follicles.5- Binding of anti-thyroid Ab (anti-thyroglobulin and anti-peroxidase) followed by Ab dependent

cellular cytoxicity.

The disease associated with hypothyroidism in middle age women in area with normal iodine level diet, patient with hashimoto are increase risk for developing other autoimmune disease risk (autoimmune adrenalitis and type 1 IDM), SlE…. Myasthenia gravis, Sjogren syndrome, also thyroid carcinoma and B cell lymphoma in thyroid gland occur with hashimoto disease. (In hashimoto more T3, more T4 and less TSH) Hashitoxicosis at beginning, later on, less T3, less T4 and more TSH) and decrease radioactive lodine uptake by rodioidine scan.

Autoimmune thyroiditis:

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Called painless thyroiditis postpartum thyroiditis i.e. after pregnancy. Mild hyperthyroidism in middle age women.

The patient have circulating auto Ab against peroxidase some cases can evolve into hypothyroidism and thyroid histology similar to Hashimo thyroiditis with diffuse lymphocytic infiltration replace thyroid tissue.

Subacute lymphocytic thyroiditis:

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Dequervian thyroiditis ,also occur in middle age women , it believed to be triggered by viral infection, it mostly occur in summer in association with other viral infection measles, mumps, adenovirus, other viral infection when exposure to viral Ag or thyroid Ag following virus induced tissue damage , cytotoxic T cells cause damage to thyroid follicles, in contrast to autoimmune thyroid disease, it is immune mediated viral initiated process, associated with pain granuloma.

The thyroid gland enlarged due to early active inflammatory response, with lymphoid follicles replaced by lymphocytes and activated macrophages with multi-giant cells formation and plasma cell replace the damaged follicles together with fibrosis. Similarly have more T4,more T3, and less TSH similar to Graves disease but radioactive iodine uptake decreased.

Granulomatous thyroiditis:

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With fibrosis involving the thyroid gland the presence of hard and fixed thyroid mass cause simulates thyroid carcinoma. It may be associated with fibrosis in other sites of body such as in retro-peritoneum a manifestation of systemic autoimmune IgG4 related disease.

Riedel thyroiditis:

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Is most common cause of endogenous hyperthyroidism characterized by:1- Diffuse enlargement of thyroid gland (thyrotoxicosis) opthalmopathy and dermatopathy (pretibial myxedema).2- It is an activation of thyroid epith. Cells by autoantibodies to TSH receptor that mimic TSH action (thyroid stimulating immunoglobulin).3- Diffuse hyperplasia and hypertrophy of follicles and lymphoid infiltration, glycosaminoglycan deposition and lymphoid infiltration responsible for opthalmopathy and dermatopathy.4- Laboratory features less TSH, more T3 and more T4 .

Graves' disease (Hyperthyroidism)

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5- In women more than male with age 20-40 years old.6- Genetic factor important in Graves ' disease in monozygotic than dizygotic twins similar to Hashimoto thyroiditis.7- Hyperthyroidism occasionally resulted from increase T3 (T3 thyrotoxicosis) but T4 may br decreased in those patients.8- In pituitary associated (secondary)hyperthyroidism TSH-normal or raised, during treatment with thyrotropin-releasing hormone (TSH), lead to increase TSH level (normal raise)and excludes secondary hyperthyroidism.


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9- Autoimmunity are important in exophthalmos protrusion of eye ball (opthalmopathy ) due to :

1. Infiltration of retro orbital space by mononuclear cells.2. Edema and inflammation, swelling extraoricular muscles.3. Accumulation of extra cellular matrix component such as hyaluronic acid and chondroitin (Glycosaminoglycans)mundereffect of CD4+.4. Fatty cells infiltration these change displace eye ball forward, all these changes interfere with extraoricular muscle function.


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Thyroid acini epith showed hyperplasia epith tall and project in the lumen with papillae, lymphoid (T, B cells) infiltrate the interstitial tissue with germinal centers, administration of iodine cause involution of epith. Treatment with propylthioracil stimulate TSH secretion and reduce hyperplasia and hypertrophy of epith.

Histologically:

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lymphocytes infiltration and glycosaminoglycansdeposition,similar to exopthalmia.Graves's patients are at risk for developing other autoimmune disease such SLE, pernicions anemia, type 1 DM and Addison disease, other diseases, heart hypertrophy and ischemic changes. Thyroid of myopathy, over activity of sympathetic nervous system.In grave disease increase iodine uptake by radioiodine scan

Treatment by: propylthiouracil, radioiodine and surgery.

The dermatopathy and pretibial myxedema due to:

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Autoimmune disease, in which extensive destruction of Beta. Cells in pancreas and insulin deficiency there is circulating auto Abs against Beta cells Ags of pancreas and against insulin detected in affected patients.

Type 1DM: (diabetes mellitus):

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Resulted from destruction of:

Adrenal cortex, both sexes affected but much common in whites and women. In which auto Abs against steroidogenic cells cause their destruction and autoantibodies against steroidogenicenzyme (21 hydroxylase, 17 hydroxylase ) so histologically scattered residual cortical cells in C.T network and lymphocytes infiltrate.

Addison disease (primary chronic adrenocortical insufficiency) (autoimmune adrenalitis)

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it occur with either autoimmune:

1- Polyendocrine syndrome type I (autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy) with mucocutaneous candidiasis, abnormalities of skin, dental enamel and nails (ectodermal dystrophy) with organ specific autoimmune disorders (autoimmune adrenalitis, hypoparathyroidism, hypogonadism, pernicious anemia) with destruction of target organs.2- Autoimmune Polyendocrine syndrome type II occur in association with adrenal insufficiency, autoimmune thyroiditis or type 1DM but not candidiasis and not ectodermal dystrophy and not autoimmune hypoparathyroidism develop.


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• In Addison disease autoantibodies against IL17,IL22 which produced by TH17 these cytokines important for defence against fungal infection so candidiasis develop in Addison disease.

• Autoantibodies against steroidogenic enzyme 21 hydroxylase and 17 hydroxylase, these autoantibodies are important in destruction of these cells.

• In Addison disease the level of mineralocorticoid and glucocorticoid are decreased, so weakness, fatigue, GIT, disturbances,K+ more(Retention), less Na(Loss) and hypoglycemia due to decrease glucocorticoids.

• Hyperpigmentation of skin,sun exposed area;neck, knee, elbow and knuckles(at pressure point)is pathognomonic, caused by elevation of proopimelanocortin(POMC) which derived from pituitary gland and precursor for ACTH and melanocytes stimulating hormone,ACTH high, Skin pigmentation.

• In contrast the hyperpigmentation not occur in person with adrenocortical insufficiency caused by primary pituitary or hypothalamus disease.


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Any disorder in pituitary gland and hypothalamus reduce ACTH lead to hypoadrenalism characterized by no hyperpigmentation,low cortisol and androgen level but normal or near normal aldosterone synthesis, normal Na and K, decrease ACTH level can occur alone by which differenciatedbetween Addison (normal level)and secondary adrenocortical insufficiency (low level).

In Addison the destruction of adrenal cortex reduces response to exogenous giving ACTH where as, in secondary hypofunction there is a prompt rise in plasma cortisol level.

Secondary adrenocortico Insufficiency:

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1- Is characterized by antibodies to parietal cells and intrinsic factor seen in serum and gastric mucosa.2- Reduced pepsinogen concentration.3- Endocrine cell hyperplasia.4- VIT B12 deficiency.5- Defective gastric acid secretion (achlorhydria).

Loss of parietal cells, CD4 against parietal cell component cause injury mucosal damage of body and fundus and mucosal atrophy, lymphocytes and macrophage infiltration together with plasma cells in association with lymphoid aggregation, also intestinal metaplasia with goblets cells and columnar absorptive cells in mucosa.

Autoimmune gastritis:

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1- Type I hypersensitivity reaction or anaphylaxis:

Occur when exposure to an Ag result to formation IgE bind on mast cells when subsequent exposure to same Ag degranulation of mast cells and release of mediator increase vascular permeability so edema and smooth muscle contraction. It occur in two phases;

1. Early within 5-30 minutes.2. Late phase 2-24 hrs. With mononuclear cells, eosinophils and neutrophils infiltration causing mucosal damage.

3) Hypersensitivity or immunological injuries:

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1- Histamine.2- Serotonin.3- Lipase.4- Proteinase.5- Kinins.6- Eosinophils chemotactic factor.7- Neutrophils chemotactic factor.8- Leukotriene and prostaglandin.

Clinical examples:Reaction to penicillin, bee stings lead to skin rash, nausea, vomiting, facial swelling, hypotension, and tachycardia.

Among mediators:

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Antibodies directed against Ag on cells or extra cellular matrix Ag either endogenous or exogenous their mechanisms:Complement dependent reaction in which Ab bound to Ag and fix complement, cause cell lysis by promote phagocytosis.Ab dependent cell- mediated cytotoxicity.These include neutrophils, eosinophils, macrophages and natural killer cells have receptors for IgG and mediate removal of Ag.Clinical examples:Blood transfusion reaction, autoimmune hemolytic anemia.Ab mediated cellular dysfunction.Abs them self-affect function of Ag. Examples Graves ' disease is due to Ab activate thyroid stimulating hormone receptor, result in hyperthyroidism myasthenia a gravis due to Abagainst acetylcholine receptor impair neuromuscular transmission.

2-Type II hypersensitivity, cellular cytotoxicity or cellular lysis:

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3-Type III hypersensitivity:

The Ab bind to Ag forming the immune complexes (Ag either exogenous- viral proteins or endogenous DNA. the immune complexes from in situ in tissue or circulate in blood and deposited and cause tissue damage. The immune complex activate complement system and enhance the immunological tissue damage examples: glomerulonephritis.

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4- Type IV hypersensitivityMediated by T cells sensitized against Ag and killing by CD8+, in this mechanism CD4+ helper,T cell sensitized to Ag from previous exposure then secrete interferon gamma IFN- ᵞ produce by these cells promote further THI, IFN- ᵞ cause activation of macrophages, activated macrophage secreted tumor necrosis factor (TNF) cause tissue damage.IL12 secreted from the dendritic cell and macrophages cause differentiation of TH1 cells,helper cell APCs produce IL1,IL6 and close to IL12(IL23) stimulate T cells to produce TH17 and TH1,TH17 has as neutrophil component TH1 produce IFN-ᵞ, stimulation of macrophages and T cells lead to granuloma accompanied by epitheloid and multinucleated giant cells formation with central caseation.Clinical examples T.B, leprosy, fungal and parasitic infection.

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The sensitized CD8 cell kill Ag bearing cells such as viral infected cells or tumor cells the Ag represented by MHC I major histocompatibility complex 1 Ag.CD8 kill Ag bearing cells by either perforin produce holes in plasma membrane of cell bearing Ag or tumor cells or by activation of complement system.

Cell mediated cytotoxicity:

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Amyloid is a hyaline material deposited in intercellular spaces around cells rather than in cells. special stain of amyloid is Congo red.

Chemical nature of amyloid:AL amyloid light chain derived from plasma cells (Amyloid A protein) in immunological disorderAA amyloid associated protein derived serum protein precursor formed in liver in chronic infections.AB in brain Alzheimer disease (Amyloid b protein) or (Beta amyloid protein).transthyretin (TTR) serum protein bind to *thyroxin and retinol,transport and deposited in heart (Heredofamilial amyloidosis).B2 microglobulin occur with long term hemodialysis, is component of MHC class1 molecules.

4) Amyloidosis:

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*Accumulated in: spleen, kidney and liver.In H&E amyloid stain eosinophilic but in Congo red pink colour under light microscope but green birefringence under polarizing microscope.Causes:A. long continued infection such as T, B and leprosy.B. prolonged immunological reaction in which hypergabulinemia.Organs involved are mostly:A. Spleen either focal in white pulp termed sago spleen or diffuse involve all splenic tissue i.e. red and white pulp termed bacon amyloid.B. Liver occur in mid zonal region of liver lobules in spaces between liver cells and sinusoid endothelium.C. In kidney amyloid deposited in glomeruli and in the wall of blood vessels.

4) Amyloidosis:

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A. Primary → immunological associated with multiple myeloma (malignant plasma cells) associated with myeloma protein (M protein) and light chain amyloid known as bence jones protein.B. Secondary amyloid occur with chronic infection.C. Endocrine amyloid in case of thyroid carcinoma and pancreatic carcinoma.D. Familial or hereditary amyloid genetic disease.E. Senile amyloid of aging amyloid.

Amyloid may be:

lecture 12 immunopathology

Education