Immunopathology

• Hypersensitivity• Autoimmunity• Immunodeficiency

• Primary • Secondary

Hypersensitivity

• In hypersensitivity, the antigens are not destructive, but the responses to them cause tissue damage • 4 types (1-4)• Antigen can be exogenous or endogenous (self)

Type I

• IG-E mediated response.• Requires repeated exposure to allergen• Immediate and late responses (both mediated by mast cells)• Immediate (30mins – 1hr): vasoactive amines, lipid mediators• Late phase response (2hr-24hrs): mediated by cytokines and includes:

• Eosinophils • Basophils• TH2 activation

Type I

• Localized • Asthma, urticaria, allergic rhinitis.

• Systemic• Anaphylaxis

• Systemic vascular dialation and leakage w/ drop in BP.• Edema drop in BP (loss of fluid)• Bronchial constriction (mediated by LTC4/D4/E4)• Runny nose, wheezing, swelling, coughing, sneezing, itching, vomiting.• Key players?

• Mast cells, IG-E antibody, inflammatory mediators secreted by mast cells.

Type 1: predisposition

• Atopy = a predisposition to develop localized immediate hypersensitivity reactions to inhaled and ingested antigens • Atopic individuals tend to have: • High serum Ig-E • More IL-4-producing TH2 cells• 50% of patients have a family history of allergies

Type II- antibody mediated

• Antibody mediated reaction. IG-G/M bound to cells in our bodies opsinize cells for phagocytosis by MQs. We start initiating an immune response against our own cells and therefore destroy our tissues.• Side effects of drugs (penicillin), transfusion (you’re getting antibodies

that will target your cells and initiate an immune response against them).• Erthyroblastosis fetalis • Autoimmune hemolytic anemia, thrombocytopenia. • Pernicious anemia (IF).

Type III- Antibody-Antigen complex

• Mediated by antigen-antibody complex deposits in tissues.• The recruited neutrophils and monocytes cause tissue damage.• Local response is called arthus reaction (cutaneous vasculitis)• Systemic reaction is known as serum sickness• 3 phase:• Phase 1 Immune complex formation• Phase 2 immune complex deposition• Phase 3 immune complex mediated inflammation and tissue damage.

Examples:Rx to penicillin most common cause of serum sickness in US.Use of horse serum from immunized horses for immunization against diptheria.

Type IV- delayed type

• Cell mediated and not antibody mediated!!• Take 2-3 days to develop• CD4 TH1 cells and sometimes CD8 T cells respond to the tissue

antigens by secreting cytokines that stimulate inflammation and activate phagocytes.• Delayed type hypersensitivity:• PPD skin test for TB• Insect venom.

• Contact hypersensitivity:• Small molecules like Nickel and poison Ivy.

Autoimmune Diseases

• Chronic diseases caused by immune responses directed toward autologous (self) components of the body. • Involves loss of self tolerance. • More common in females than males…Ratio of 9-10:1• Except for ankylosing spondylitis (More common in males)

• Classically affects women of childbearing age • Type II Autoimmune response: autoimmune hemolytic anemia.• Type III autoimmune response: Lupus.• Clinically progressive with relapse and remissions.

Lupus

• Chronic, systemic autoimmune disease.• Flares and remissions are common.• An example of type III HSR (antibody-antigen complex deposits

damage tissues).• Autoantibodies to cell surface/cytoplasm/nucleus (nucleic acids and

nucleoprotein particles).• Almost any tissue can be involved.

Lupus

• Classical signs/symptoms:• Malar “butterfly” rash/ discoid rash, especially upon exposure to sunlight.• Stiff fingers and hips in morning• Associated with low complement.• High blood ANA titer 1:1280 (Highly sensitive).• Anti dsDNA antibodies (Highly specific)• Antibody-antigen complexes can be deposited in kidneys and joints (small

vessels) resulting in glomerulonephritis and arthritis respectively. • Management: corticosteroids to suppress the immune response.

Rheumatoid arthritis

• Chronic, systemic autoimmune disease.• An example of type IV HSR- cell mediated.• More common in women• Rheumatoid factor (Ig-M antibody against the Fc region of Ig-G;

marker of tissue damage and disease). Present in 80% of patients with Lupus.• Progressive destruction of cartilage and bone.• Symmetric involvement of joints; TMJ in 50-60% • Occurs with other autoimmune diseases.

Rheumatoid arthritis

• White blood cells infiltrate into the synovium : CD4/8, B cells, neutrophils, macrophages. All together mediate damage.• Autoimmune CD4 get activated by dendritic cells, which then activate

macrophages, which accumulate in synovium.• Pro inflammatory mediators and proteinases and collagenases

produced by activated cells destroy tissue in joints.

Graves’ Disease

• Heat intolerance, nervousness, irritability, weight loss.• Thyroid enlargment.• Autoimmune? Antibody production that bind to TSH receptors…• CD4 TH2 response.• Tx: Drugs that inhibit thyroid function, thyrodectomy.

Hashimoto’s

• Can’t make thyroid hormone. • CD4 TH1 response: both antibodies and effector T cells for thyroid

antigens produced.• Lymphocytes infiltrate and we get progressive destruction of normal

thyroid tissue.• Hypothyroidism.• Tx: replacement therapy.

Type 1 DM

• Selective destruction of insulin producing cells in pancreas : islets of Langerhans• Antibody and T-cell responses against insulin, glutamic acid

decarboxylase, and other specialized proteins of the pancreatic β cell. • CD8 T cells mediate β-cell destruction, gradually decreasing the

number of insulin-secreting cells. Individual islets become successively infiltrated with lymphocytes. • Disease begins when there are insufficient β cells to provide the

insulin necessary to control the level of blood glucose

Autoimmunity and infections: Rheumatic fever• Infection with S. pyogenes• Same antibodies made against S. Pyogenes react to epitopes present

on human heart, joint, and kidney.• When bind to self tissue activate complement and generate acute

inflammation Rheumatic fever

Immunodeficiencies

• Primary:– Most are congenital – Most are inherited– Often significant family history– Can present initially in children and adults– Some are combined with other congenital defects • Secondary:– Induced by environmental, infectious or iatrogenic factors– Common factors: malnutrition, HIV infection, radiation, chemotherapy, cancer.

Primary immunodeficiency

• Most are genetically determined.• Most common is IgA deficiency.• Blood cell count with differential is #1 for the diagnosis of primaries.• Therapy and prophylaxis always require anti microbial.• Other TX: specific for disease, may include: replacement of

immunoglobins, or stem cell transplantation.

Primary

• X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia) • Common variable immunodeficiency • Isolated IgA Deficiency• Hyper-IgM Syndrome• DiGeorge Syndrome (Thymic Hypoplasia) • Severe Combined Immunodeficiency

• Deficiencies in Phagocytosis Leukocyte adhesion deficiency

Missing integrins, cant migrate into tissues. Can’t clear infections persistent periodontal/gingival infection.

NeutropeniaDrugs: Anti-cancer chemotherapeutic agents, antibiotics, other Infections: Viral hepatitis A and B, rubella, measles, varicella, HIV, typhoid, TB, etc.

Destruction of bone marrow by malignancies

Chronic Granulomatous Disease

• Phagocytes cannot produce superoxide radical (lack NADPH oxidase which converts oxygen to superoxide anion). • Chronic infections with granuloma formation • Bacterial infections; fungal infections; foreign body (non-infectious);

hypersensitivity reactions

Secondary Immunodeficiencies

• Environmental • Malnutrition, radiation

• Infections • Human immunodeficiency virus (HIV), other microorganisms

• Iatrogenic • Chemotherapeutic agents, immunosuppressive drugs, radiation therapy • Tissues Very Sensitive to Ionizing Radiation: any cells that undergo a lot of cell

divisions.

AIDS

• Esophageal candidiasis (bronchi, trachea or lungs) • Deep fungal infections: Coccidioidomycosis, • Cryptococcosis, Cryptosporidiosis • Cytomegalovirus disease • HSV longer than 1 month • Kaposi’s sarcoma (HHV-8 associated) (<60yrs) • Lymphoma (B Cell - EBV associated)

Immunodeficiency Secondary to HIV: Mechanisms

• Infected cells: • Receptor: CD4, co-receptors: CCR5, CXCR4

• Clinical latency: Active viral replication in lymphoid tissue, spreading from cell to cell • How do you measure? CD4+ lymphocyte counts, viral load, activation

markers on CD8+ T cells • Persistent T cell activation leads to increased depletion rates • Depletion of naive T cell pool (thymus involution after puberty)

DM

• Accumulation of glycosylation products in vessel walls • T cell function is depressed • Neutrophil function is depressed • Adherence, chemotaxis, phagocytosis, anti-oxidant activity

• Oral problems: accelerated periodontal disease, poor healing, candidiasis • Zygomycosis (rhizopus) in diabetic patient with ketoacidosis AKA

Mucormycosis

Iatrogenic Cause of Immunodeficiency Immunosuppressive Drugs

• Organ transplantation• Cyclosporin: blocks (NFAT), which is required for transcription of cytokine genes

(IL-2)- Blocks T –CELL activatio!• Tacrolimus – Inhibits IL-2 and therefore blocks T-cell activation• Azathioprine: Inhibits leukocyte development from bone marrow precursors), • Corticosteroids Block inflammation by blocking NFKB and therefore cytokine

production. • Rapamycin and mycophenolate: Inhibit lymphocyte proliferation

• Cancer chemotherapy • affects dividing cells in marrow

• Corticosteroids • Inhibits leukocyte infiltration at the site of inflammation • Suppresses humoral immune responses • Affects mediators of inflammation such as prostaglandins and leukotrienes