Hypersensitivity Reactions - Nelson Flashcards
Define innate immunity.
Pre-existing defense mechanisms present to prior infection that have evolved to recognize microbial pathogens and protect the individual against infection.
Define adaptive immunity.
Reactive immune mechanisms that are stimulated by (adapt to) microbes and other foreign antigens, and are capable of recognizing microbial and nonmicrobial substances.
What are the key components of innate immunity?
- Epithelial barriers
- Phagocytic cells (neutrophils, monocytes/macrophages)
- Eosinophils, basophils, mast cells
- Dendritic cells
- Natural killer cells
- Innate lymphoid cells
- Plasma proteins
- complement system
- c-reactive protein
- lung surfactant
What are the two types of adaptive immunity?
- Humoral immunity
- protects against extracellular microbes and toxins
- Cell-mediated (cellular) immunity
- protects against against intracellular microbes, tumor cells
What is the function of T-lymphocytes?
- recognize a specific cell-bound antigen by means of an antigen specific T-cell receptor
- monoclonal (neoplastic) proliferations will have the same TCR gene rearrangement
What is the function of CD4+ T-cells?
- Helper T lymphocyte (via cytokine release)
- activate macrophages (IFN-gamma)
- induce inflammation
- activate (proliferation & differentiation) of T and B lymphocytes (IL-4)
What is the function of CD8+ T-cells?
- Cytotoxic T lymphocyte
- kill infected cell
- release perforin, granzymes, and granulysin
- activate caspace cascade
- kill infected cell
What is the function of regulatory T lymphocytes?
- suppression of immune response
- release IL-10 & TGF-beta
What is the function of B-lymphocytes?
- Recognize antigens
- proliferate and differentiate into antibody-secreting plasma cells
- neutralize microbes and toxins
- opsonize microbes
- phagocytose opsonized microbes
- antibody-depended cytotoxicity
- lysis of microbes via complement system
What is the function of Natural Killer Cells?
- Kill cells missing self markers of MHC Class I
- Cytolytic granule-mediated cell apoptosis
- Antibody-dependent cell-mediated cytotoxicity
What are the functions of Dendritic Cells?
- Capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes
- Present antigen to T-cell
- Activate T-cells (secrete IL-2)
What are Generative Lymphoid Organs (primary or central)?
Sites where T and B lymphocytes mature and become competent to respond to antigens:
- Thymus - for T lymphocytes
- Bone marrow - for B lymphocytes
What are Peripheral Lymphoid Organs (secondary)?
Sites where the adaptive immune response is initiated:
- lymph nodes
- spleen
- mucosal and cutaneous lymphoid tissues
- GI tract
- respiratory tract
- skin
What happens to the follicles in lymph nodes when B lymphocytes respond to an antigen?
- Follicle develops a germinal center
- Becomes hyperplastic = Reactive Follicular Hyperplasia
What is the physiologic function of Major Histocompatibility Complexes (MHC)?
- Display peptide fragments of proteins for recognition by antigen specific T cells
- MHC Class I: display antigens that are recognized by CD8+ T-lymphocytes and NK cells
- MHC Class II: display antigens that are recognized by CD4+ T lymphocytes
Where are the genes for Major Histocompatibility Complexes located in humans?
- Chromosome 6 = Human Leukocyte Antigen (HLA) Complex
- MHC Class I: coded by HLA-A, HLA-B, and HLA-C genes
- MHC Class II: coded by HLA-DP, HLA-DQ, and HLA-DR genes
What are the two uses of HLA testing?
-
Can be used to determine disease risk
- e.g. 90% of patients with ankylosing spondylitis are positive for HLAB27
-
Used in transplantation workup
- 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
What is a hypersensitivity reaction?
- excessive, injurious pathologic immune reaction to the repeat exposure of an antigen
- exogenous (environmental)
- endogenous (self-antigens, autoimmune diseases)
What do hypersensitivity reactions usually result from?
Imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses.
What happens in Type I Hypersensitivity reactions (allergic reactions)?
-
Mast cell degranulation
- due to repeat exposure to the antigen (allergen)
- Mediated by IgE antibody-dependent activation of mast cells
Define atopy.
Predisposition to develop immediate hypersensitivity reactions.
(susceptibility to immediate hypersensitivity reactions is genetically termined)
What is the difference between the immediate phase reaction and late phase reaction in Type I Hypersensitivity reactions?
- immediate reaction:
- eosinophils secrete major basic protein and eosinophil cationic protein (toxic to epithelial cells)
- vasodilation
- congestion
- angioedema
- Late phase reaction:
- amplifying and sustaining the inflammatory response via release mediators from activated mast cells
- inflammatory infiltrate rich in eosinophils, neutrophils, and T-cells
What is a localized allergic reaction?
only affects particular body systems
- respiratory system
- intestinal mucosa
- skin
What are some common examples of localized allergic reactions?
- Allergic rhinitis
- Sinusitis
- Bronchial asthma
- Food allergies
- Urticaria
What are three common features in systemic anaphylaxis?
- laryngeal edema
- bronchospasm
- decreased BP
What is the mechanism behind systemic anaphylaxis?
- Massive mast cell activation and degranulation releasing:
- Histamine
- Proteases
- Chemotactic factors
- Results in vasodilation, vascular leakage, and smooth muscle spasm
What are the clinical findings in systemic anaphylaxis?
- Acute onset of illness (minutes-hours)
- Involvement of the skin, mucosal tissue, or both
- hives, pruritus, flushing, angioedema
- Respiratory compromise
- dyspnea, wheeze, stridor
- Reduced BP
- GI symptoms (abdominal pain, vomiting)
What are some of the common inciting agents in fatal systemic anaphylaxis?
- Death due to:
- asphyxiation (deficient oxygen supply to body due to abnormal breathing)
- acute respiratory failure (bronchial restriction/obstruction)
- cardiovascular collapse
What is a Type II Hypersensitivity Reaction? Mechanism of injury?
- Antibodies react with normal or altered cell surface antigens, or with antigens in the extracellular matrix
- autoantibodies
- drugs
What is Goodpasture’s syndrome?
- Make antibodies to glomerular basement membrane components
- linear pattern of deposition
What is a Type III Hypersensitivity Reaction? Mechanism of injury?
- Deposition of antigen-antibody complexes that form in the serum
- circulating immune complexes are deposited in vessel walls
- exogenous
- endogenous
- circulating immune complexes are deposited in vessel walls
Why are the clinical manifestations of Type III Hypersensitivity Reactions diverse?
What is a Type IV Hypersensitivity Reaction? Mechanism of injury?
- Inflammation resulting from cytokines produced by CD4+ T lymphocytes and cell killing by CD8+ T lymphocytes
- Mechanisms:
- CD4+ T cell-mediated inflammation
- recruits/activates macrophages and neutrophils
- CD8+ T cell-mediated cytotoxicity
- kill antigen-expressing target cells
- CD4+ T cell-mediated inflammation
What are the mechanisms of injury in Type II Hypersensitivity Reactions?
- Opsonization and phagocytosis
- Complement- and Fc receptor-mediated inflammation
- Antibody-mediated cellular dysfunction
What is the mechanism of injury in Type III Hypersensitivity Reactions?
- Immune complex formation
- Immune complex deposition
- Immune complex-mediated inflammation and tissue injury
- e.g. fibrinoid necrosis
Low levels of what are used to monitor disease in systemic immune complex-mediated diseases (type III hypersensitivities)?
C3
(low levels indicate active disease)
How do granulomas form?
- Strong activation of T lymphocytes
- Recruitment of monocytes from the blood to become activated macrophages in the tissue
- chronic inflammation consisting of a microscopic aggregation of macrophages
- macrophages transform into epithelial-like cells (histiocytes)
- histiocytes fuse to form multi-nucleated giant cells
What are the three types of granulomas?
- Foreign body granulomas
- Caseating granulomas
- Non-caseating granulomas
What do foreign body granulomas look like?
- See foreign material within histiocytes/giant cells
- called “foreign body giant cell reaction”
What are caseating granulomas?
- Granulomas that induce cell-mediated immune response with central necrosis
- usually associated with infection
- e.g. mycobacterial, fungal infections
- usually associated with infection
What are non-caseating granulomas?
- Granulomas that induce cell-mediated immune response without central necrosis
- e.g. Sarcoidosis, Crohn’s disease
How can light-chain expression be used to determine if a B-lymphocyte proliferation is clonal?
- Monoclonal (neoplastic) proliferations typically produce/express only one type of immunoglobulin
- Immunoglobulin light chain expressed by a neoplastic, monoclonal B lymphocyte population will be of either kappa or lambda type
- LIGHT CHAIN RESTRICTION
How does flow cytometry detect the presence of a monoclonal population?
- Detects light chain restriction
- Quantifies cells in a stream of fluid
- fluorescent labeled antibodies can bind to specific antigens on the cells
- electronic detection device records the cell types & percentage of each
- Can be performed on fresh/unfixed tissue, blood, or body fluids
How does serum protein electrophoresis detect the presence of a monoclonal population?
- Quantifies the fraction of certain proteins in serum using an electrical field to separate the proteins in the serum into groups of similar size, shape & charge
- measures specific proteins in the blood to help identify some diseases
- Albumin
- Alpha 1, Alpha 2
- Beta
- Gamma
How does immunofixation electrophoresis detect the presence of a monoclonal population?
- allows the detection of monoclonal antibodies representative of diseases
- deposit the serum on a gel
- apply electric current that allows the separation of proteins according to their size and charge, antibodies specific for each type of immunoglobulin were laid upon the gel
How does kappa and lambda in situ hybridization detect the presence of a monoclonal population?
- Dark-staining areas indicate Kappa
- Light-staining areas indicate Lambda
- If only light staining = kappa light chain restriction
- If only dark staining = lambda light chain restriction
What is the benefit of doing T-cell receptor gene rearrangement studies and B-cell immunoglobulin gene rearrangement studies?
- Help distinguish a B lymphocyte reactive proliferation from a monoclonal (neoplastic proliferation when light chain restriction is difficult to detect
What are the five pillars of cancer treatment?
- Surgery
- Chemotherapy
- Radiation
- Molecular targeted therapy
- Immunotherapy
What are some examples of Type II Hypersensitivity diseases?
- Autoimmune hemolytic anemia
- Pemphigus vulgaris (antibody-mediated destruction of epidermal cadherin)
- Myasthenia Gravis (antibody-mediated destruction of acetylcholine receptor)
- Graves disease (antibody-mediated stimulation of TSH receptors)
- Insulin-resistant diabetes (antibody inhibits binding of insulin)
- Pernicious anemia (antibodies neutralize intrinsic factor of gastric parietal cells –> decreased absorption of vitamin B12)
What are some examples of Immune Complex-Mediated Disease (Type III Hypersensitivity)?
- Systemic Lupus Erythematous
- Poststreptococcal glomerulonephritis
- Reactive arthritis
- Serum sicknus
What are some examples of T Cell-Mediated Diseases (Type IV Hypersensivitiy)?
- Rheumatoid arthritis
- Multiple Sclerosis (myelin destruction by activated macrophages due to TH1 & TH17))
- Type 1 Diabetes
- Inflammatory Bowel Disease
- Psoriasis (inflammation by TH17 cytokines)
- Contact sensitivity
