Week 3 Flashcards
o Activated lymphocytes:
differentiate into effector cells once bound to antigen, which eliminate the offending organism, and memory cells, which can be reactivated upon second exposure.
o Effector Lymphocytes:
produced by the differentiation of T cells and produce distinct sets of cytokines and perform different functions (i.e. Th1, Th2, Th17)
o Memory Lymphocytes:
are expanded pools of antigen-specific lymphocytes which respond faster and more effectively when re-exposed to antigen than do naïve cells. One goal of vaccination is to generate memory cells
• Describe how light chain expression can be used to determine if a B-lymphocyte proliferation is clonal. Describe the use of T-cell receptor gene rearrangement studies and B-cell immunoglobulin gene rearrangement studies.
o B lymphocytes clonal proliferations typically express only one type of immunoglobulin and thus only one light chain (kappa or lambda) since light chains do not change upon class switching. o T lymphocytes recognize specific bound antigen through binding to their TCRs • For both B and T lymphocytes, due to clonal proliferation actions performed by both cells it can be difficult to distinguish between normal clonal proliferation and clonal neoplastic proliferation; however, Ig and TCR gene rearrangement analysis can help, respectively
o Generative lymphoid organs
sites where T and B lymphocytes mature and become competent to respond to antigens (bone marrow and thymus)
o Peripheral lymphoid organs
sites where adaptive immunity is initiated (lymph nodes, spleen, mucosal and cutaneous lymphoid tissues)
• B cells found in follicles of lymph node; T cells in paracortical region
• Lymphocytes constantly recirculate between tissues and home to particular sites
o Major Histocompatibility Complex (MHC)
physiologic function is to display peptide fragments of proteins for recognition by antigen specific T cells
• MHC genes found on chromosome 6
• MHC aka human leukocyte antigen (HLA) complex and produce membrane bound glycoproteins which are found on all nucleated cells (except mature RBCs)
• MHC system is highly polymorphic (many different alleles of each MHC gene)
• MHC I: display proteins derived from the cytoplasm (viral antigen); recognized by CD8+ T cells and NK cells; coded by HLA-A, HLA-B, and HLA-C genes
• MHC II: display antigens that have been internalized into vesicles; recognized by CD4+ T cells; coded by HLA-DP, HLA-DQ, DLA-DR genes
o HLA Testing Uses
• A variety of diseases are associated with the inheritance of certain HLA alleles; HLA testing can be used to determine disease risk
• Used in the transplantation workup as close matches of HLA-A, HLA-B, HLA-C and HLA-D in both the donor and graft recipient increase the chance of graft survival
o Induction and regulation of immune responses involve multiple interactions that are mediated by cytokines
• Describe the key steps and functions of cell-mediated immunity
- Dendritic cells (DCs) capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the DCs mature, and express high levels of MHC molecules and costimulators.
- Naïve T cells recognize MHC-associated peptide antigens displayed on DCs. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity.
- CD4+ effector T cells of the TH1 subset recognize the antigens of microbes ingested by phagocytes, and activate the phagocytes to kill the microbes.
- CD4+ T cells also induce inflammation.
- CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm of the infected cell.
- Not shown are TH2 cells, which are especially important in defense against helminthic infections. Some activated T cells differentiate into long-lived memory cells.
- Following T cell migration, the activated T cell causes: inflammation, macrophage activation (killing ingested microbes), and T cell-mediated killing of infected cells
• Describe the key steps and functions of humoral immunity.
- Naïve B lymphocytes recognize antigens, and under the influence of TH cells and other stimuli (not shown), the B cells are activated to proliferate and to differentiate into antibody-secreting plasma cells.
- Some of the activated B cells undergo heavy-chain class switching and affinity maturation, and some become long-lived memory cells.
- Antibodies of different heavy-chain classes (isotypes) perform different effector functions, shown on the right
List the four types of hypersensitivity reactions
individuals previously exposed to an antigen become sensitized and upon repeat exposure(s) some individuals develop a pathologic immune reaction to the antigen
• Exogenous and endogenous antigens elicit hypersensitivity reactions
• Development of Hypersensitivity Diseases is often associated with inheritance of particular susceptibility genes (HLA and non-HLA genes)
• Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to limit such responses.
• Hypersensitivity diseases can be classified on the basis of the immunologic mechanism that mediates the disease
Type of Reaction Prototypic Disorder Immune MOA Pathologic Lesions
Immediate
(Type I) Anaphylaxis; allergies Production of IgE Ab → release of vasoactive amines from mast cells; recruit inflammatory cells later Vascular dilation, edema, smooth muscle contraction, mucus production, tissue injury, inflammation
Antibody-mediated
(Type II) Autoimmune hemolytic Anemia; Goodpasture syndrome Production of IgG, IgM → binds to Ag on target cell/tissue → phagocytosis/lysis of target cell Phagocytosis and lysis of cells; inflammation
Immune Complex-mediated
(Type III) SLE, Poststreptococcal Glomerulonephritis, Serum sickness Deposition of Ag-Ab complexes → complement activation → recruit leukocytes to release enzymes and toxic molecules Inflammation, necrotizing vasculitis (fibrinoid necrosis)
Cell-mediated (Type IV) Contact dermatitis; MS, T1D, RA, IBS, TB Activated T cells 1) release cytokines, 2) initiate T cell-mediated cytotoxicity Perivascular cellular infiltrates, edema, granuloma formation; cell destruction
o Atopy
predisposition to develop localized immediate hypersensitivity reactions
• Atopic individuals tend to have higher serum IgE levels and produce more IL-4 producing Th2 cells
• Describe the mechanisms involved in the immediate and late phase reactions of type I hypersensitivity reactions.
o Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity.
• Characteristic features of immediate hypersensitivity reactions: vasodilation, vascular leakage, smooth muscle spasm
o Late phase hypersensitivity reactions are characterized by leukocyte infiltration, epithelial damage, and bronchospasm
o In some individuals, immediate hypersensitivity reactions are triggered by temperature extremes and exercise (non-atopic allergy) and do not involve T helper cells or IgE. In these cases it is believed that the mast cells are abnormally sensitive to activation by various non-immune stimuli
• Define localized allergic reaction, and list some common examples. Describe the treatment and prevention of localized allergic reactions.
o Localized reactions occur within a set, small space and include: allergic rhinitis (hay fever), bronchial asthma (atopic forms), urticarial (hives), and allergic gastroenteritis (food allergy)
o Treatment typically involves:
• Avoiding the offending allergen, if possible.
• Use of various medications, such as antihistamines, corticosteriods, agents that inhibit release of histamine from mast cells, leukotriene modifiers (to name just a few).
• In some cases, immunotherapy (desensitization therapy) is also used
• Define systemic anaphylaxis, and describe the mechanisms and clinical findings in systemic anaphylaxis. List some of the common inciting agents in fatal systemic anaphylaxis.
o Systemic anaphylaxis refers to a life threatening systemic allergic reaction typically characterized by vascular shock, widespread edema, and difficulty breathing (massive mast cell activation).
o Common inciting agents:
• Therapeutic agents (e.g. antibiotics - penicillin and cephalosporins, radiocontrast agents)
• Exposure to food products (e.g. peanuts, seafood)
• Insect toxin (e.g. bee or wasp sting)
• Latex allergy
o Clinical Findings: asphyxiation or respiratory failure due to bronchial constriction/obstruction and/or shock with CV collapse → death within minutes if untreated
• Median time for onset of symptoms and respiratory/CV collapse:
• Iatrogenic anaphylaxis (medical or surgical treatment) – 5 minutes
• Insect venom – 15 minutes
• Food-induced anaphylaxis – 30 minutes
o Treatment: IM epinephrine
• Venom immunotherapy as prevention; form of desensitization therapy: repeat injections of allergen in increasingly greater amounts results in production of IgG antibodies that can attach to allergens and prevent their binding to mast cells
• Define type II hypersensitivity reaction, and list the mechanisms of injury.
o Type II hypersensitivity reactions are caused by antibodies that react with normal or altered cell surface antigens, or with antigens in the extracellular matrix; autoimmunity
o Mechanisms of Injury:
• Opsonization of cells by antibodies and complement components cause ingestion by phagocytes
• Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products
• Anti-receptor antibodies disturb normal function of receptors (Myasthenia gravis)
Goodpasture Syndrome
target: Noncollagenous protein in basement membrane of kidney glomeruli and lung alveoli
mech of disease: Complement and Fc receptor mediated inflammation
clinical presentation:
Nephrites, lung hemorrhage
• Define type III hypersensitivity reaction, and list the mechanisms of injury. Describe some examples of this type of reaction, and explain why the clinical manifestations can be quite diverse.
o Type III hypersensitivity reactions are caused by antigen-antibody complexes which elicit inflammation at the sites of deposition.
o Mechanisms of Injury:
• The pathologic reaction begins when antigen combines with antibody in the circulation, and the circulating immune complexes are deposited in vessel walls.
• The involved antigens can be exogenous or endogenous, and the sites of involvement can be systemic or localized.
o Pathogenesis: Complement is consumed as part of the pathogenic process, and the levels of C3 can be used to monitor disease activity (low levels indicate active disease)
o Diseases associated with type III:
• SLE → antibodies to DNA
• Poststreptococcal glomerulonephritis → antibodies to glomerular basement membrane deposited by streptococcal cell wall antigens
• Polyarteritis nodosa → antibodies to antigen from hepatitis B virus
• Reactive arthritis → Ab to bacterial antigens
• Serum sickness → venom antigen is circulating and antibodies bind the venom
• SLE
antibodies to DNA
• Poststreptococcal glomerulonephritis
antibodies to glomerular basement membrane deposited by streptococcal cell wall antigens
• Polyarteritis nodosa
antibodies to antigen from hepatitis B virus
• Reactive arthritis
Ab to bacterial antigens
• Serum sickness
→ venom antigen is circulating and antibodies bind the venom
• Define type IV hypersensitivity reaction, and list the mechanisms of injury. Describe the mechanism of granuloma formation, and list some examples of this type of reaction.
o Caused by T cell mediated immunity (no antibodies involved); CD4+ or CD8+ T lymphocytes are sensitized to exogenous or endogenous antigens. The resultant T cell immune response results in cell or tissue injury
o There are two mechanisms of T cell mediated (type IV) hypersensitivity:
• Delayed-type hypersensitivity reaction
• T cell mediated cytotoxicity
o Type IV Hypersensitivity used in Mantoux Test: inject antigen from TB (dead) and look for memory T cell activation to the antigen to form a nodule; measure area of induration
• In some places the Mantoux test is being replaced by quantiFERON-TB test which involves incubated the patient’s lymphocytes for 16-24 hours with a cocktail of TB antigens
• If patient has been previously exposed to TB the T cells will release cytokines (IFNγ) which can be measured using an immunoassay
o Granulomatous Formation: APC-bound antigen presents to Th1 cell which secretes IFNγ which acts on monocytes to create giant cells which are indicative of granulomatous formation
• List the four types of genes typically mutated in cancer.
o Growth promoting proto-oncogenes
• Ex. BCR-ABL mutation in CML, K-ras in Colon Cancer, myc in Burkitt’s Lymphoma
o Growth initiating tumor suppressor genes
• Ex. BRCA1/BRCA2 in Breast Cancer, Rb in Retinoblastoma, TGF-β in pancreatic and colorectal carcinomas
o Genes that regulate apoptosis
• Ex. Bcl-2 overexpression → blocks apoptosis
o Genes involved in DNA repair (ex. PARP)
• Ex. telomerase expression to increase telomere length
• Using only a few sentences for each, list the 8 essential alterations involved in malignant transformation of cells.
o 1. Self-sufficiency in growth signals
• Cell proliferation occurs due to proto-oncogenes becoming oncogenes. These oncogenes make oncoproteins which are devoid of regulatory elements and cause transformation in cells, but do not rely on growth factor or external stimuli.
o 2. Insensitivity to growth-inhibitory signals
• When tumor suppressor genes are silenced, it is considered a LOH, which typically causes expression of an oncogene to occur.
o 3. Evasion of apoptosis
• Over expression of Bcl-2 causes the blocking of apoptosis. This is a common characteristic of 85% of B-cell lymphomas which protects the B-cells from apoptosis, allowing the B-cells to survive for long periods of time.
o 4. Limitless replicative potential
• Telomerase expression results in maintenance of telomere length which avoids senescence. Maintenance of telomeres is seen in virtually all types of malignant neoplasms.
o 5. Sustained angiogenesis
• Tumors need vasculature to grow and proliferate. Angiogenesis is required for not only continued tumor growth, but also for access to the vasculature and hence metastases. VEGF is a common angiogenesis factor.
o 6. Ability to invade and metastasize
• This process involves invasion of the ECM and vascular dissemination, homing of tumor cells, and colonization. Invasion of ECM involves breaking through the basement membrane and intravasating into the bloodstream. Once in the bloodstream, the metastasizing cells need to get out (vascular dissemination). Homing of tumor cells results in association with other tumor cells. Colonization involves tumor cells secreting cytokines, growth factors, and ECM molecules to make the metastatic site habitable for the cancer cell.
o 7. Defects in DNA repair
• Effective DNA repair mechanisms are essential to maintain the integrity of the genome. Many inherited and sporadic cancers have defects in DNA repair mechanisms that allow for mutations in other genes during cell division.
o 8. Escape from immune attack
• The immune system is involved in surveying the body for malignant cells and destroying them. For tumor cells to survive, they must evade the immune system by various mechanisms: loss/reduction of MHC molecules, immunosuppression, antigen masking, and apoptosis of cytotoxic T-cells to name a few.
• ABL-BCR fusion gene:
results in increased tyrosine kinase activity (treat with tyrosine kinase inhibitor imatinib mesylate, Gleevac). [Slide 21 pathogenesis]
• HER 2/neu
results in over expression of cell membrane epidermal growth factor receptor - EGFR (in breast cancer), treat with monoclonal antibody to Her2/neu receptor, trastuzumab (Herceptin). Need to be Her2/neu + for tx to work.
• RAS:
results in persistent activation of the RAS signal (KRAS for colon cancer; presence of KRAS in colon cancer can be predictive of lack of response to certain forms of chemotherapy). Anti-EGFR antibody only effective if have KRAS mutation
o Familial adenomatosis polyposis (FAP
Patients inherit a single APC (adenomatosis polyposis coli) mutation, and then acquire a second APC mutation. The loss of tumor suppressor function results in large numbers of adenomatous polyps in the colon and rectum during late childhood, adolescence, and early adulthood. There is a 100% risk of colorectal adenocarcinoma (mean age of carcinoma 35-40 yrs, can occur in the teenage yrs)
• Describe how overexpression of BCL-2 can lead to follicular lymphoma
o Bcl-2 protein is an anti-apoptotic protein which limits cytochrome c release. 85% of B-cell lymphomas of the follicular type carry a characteristic t(14;18) translocation which results in overexpression of the Bcl-2 protein. This mutation allows lymphocytes to evade apoptosis and survive for long periods of time. They tend to be indolent (slow growing).
