Transcript File - NYU OMS Society

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
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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
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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
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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.
Neutropenia
Drugs: 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