Hypersensitivity Flashcards
How to determine if B cell monoclonal proliferation?
including flow cytometry, serum protein electrophoresis with immunofixation electrophoresis (e.g. monoclonal spike in myeloma), kappa and lambda immunostaining, and kappa and lambda in situ hybridization study, B lymphocyte immunoglobulin gene arrangement analysis
How to determine if T cell monoclonal?
TCR gene rearrangement analysis
flow cytometry studies, or by analysis of immunostains for T lymphocyte markers on paraffin embedded tissue.
Flow cytometry performed on what
fresh, unfixed tissue
5 pillars of cancer treatment
Surgery Chemotherapy Radiation Targeted therapies Immunotherapy
Protein serum electrophoresis - what do you see in cirrhosis, myeloma, waldenstrom’s macroglobulinemia
In cirrhosis, see elevated gamma fraction but with kappa and lambda.
In myeloma, see only kappa and peak in gamma.
In Waldenstrom’s macroglobulinemia - kappa light chain restriction, M speak monoclonal
Define hypersensitivity reactions
Individuals previously exposed to an antigen are said to be sensitized; upon repeat exposure(s), some individuals will develop an excessive, injurious pathologic immune reaction to the antigen. These pathologic immune reactions are called hypersensitivity reactions, and are the basis of the pathology associated with immune diseases.
type 1 hs
immediate
type 2 hs
antibody-mediated
type 3 hs
immune complex-mediated
type 4 hs
cell-mediated
type 1 hs prototypic disorder
anaphylaxis, allergies, bronchial asthma
type 2 hs prototypic disorder
autoimmune hemolytic anemia, goodpastures
type 3 hs prototypic disorder
SLE, serum sickness, arthus
type 4 hs prototypic disorder
contact dermatitis, MS, DM 1, RA, IBD, tb
Type 1 hs definition
rapid immunologic reaction occurring within minutes after an antigen combines with antibody bound to mast cells in individuals previously sensitized to the antigen (allergic reaction).
Type 1 hs mediated by
is typically mediated by IgE antibody-dependant activation of mast cells, with degranulation and release of mast cell contents.
Type 1 hs steps
Sensitization (initial exposure to antigen – activation of B cells w/ production of IgE attaching to mast cells)
Repeat exposure causing mast cell degranulation
Late phase reaction
What do mast cells release
release of chemical mediators, causing vasodilation, vascular leakage, smooth muscle spasm, and recruitment of leukocytes, particularly eosinophils.
What do eosinophils release
secrete major basic protein and eosinophil cationic protein, which are toxic to epithelial cells.
what is late phase reaction
Activated eosinophils and neutrophils also activate mast cells to release mediators, amplifying and sustaining the inflammatory response without additional exposure to the triggering antigen (late phase reaction).
atopy
predisposition to develop immediate hypersensitivity reacti
Antigens that elicit allergic reactions
allergens
hygiene hypothesis
Incidence of allergic diseases is increasing. As this seems to be related to decreasing infections in early life, some have postulated that improved hygiene has diminished exposure to microbial antigens in early life which “educate” the immune system, setting the stage for subsequent pathologic allergic responses later in life
Mediators of immediate hypersensitivity (of type 1)
vasoactive amines, lipid mediators
Mediators of late phase reaction (of type 1)
cytokines
Non-Atopic allergy
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.
Examples of local allergic reactions
allergic rhinitis, sinusitis
bronchial asthma
Food allergies (allergic gastroenteritis)
Urticaria (often a manifestation of a systemic reaction)
systemic allergic response
anaphylaxis
anaphylaxis characterized by
fall in blood pressure with vascular shock, bronchospasm and laryngeal edema with difficulty breathing (massive mast cell activation).
death from anaphylaxis
to asphyxiation from upper airway edema or acute respiratory failure due to bronchial constriction and obstruction, and/or shock with cardiovascular collapse.
desensitization therapy
repeated injections of the allergen in increasingly greater amounts resulting in the production of IgG antibodies that can attach to allergens and prevent them from binding to mast cells.
type II caused by
antibodies that react with normal or altered cell surface antigens, or with antigens in the extracellular matrix. This can cause disease by destroying cells, triggering inflammation, or by interfering with normal function.
mechanisms of antibody-mediated injury
opsonization and phagocytosis
complement and Fc receptor
Antibody-mediated cellular dysfunction (block receptors etc)
myasthenia gravis
ach receptor (Type II)
Graves
TSH receptor (Type II)
Goodpasture syndrome
basement membrane in glomeruli of kidney (type 2)
see uniform distribution of ab to the uniformly distributed basement membrane proteins
pemphigus vulgaris
desmogleins 1 and 3 found in desmosomes –> blistering (type II)
type III cause by
immune complexes
Caused by deposition of antigen-antibody complexes which elicit inflammation at the sites of deposition.
type III pathologic reaction begins when
antigen in the circulation combines with antibody in the circulation, and the circulating immune complexes are deposited in vessel walls. In some instances, the complexes can form at extravascular sites where the antigen has been “planted” previously (called in situ immune complex deposition).
Get lumpy-bumpy fashion
lumpy-bumpy vs. smooth distribiton
lumpy-bumpy in Type III *because that’s where the antigen-ab complex lands (random, also why random/varied presentations)
smooth in Type II *because that’s how antigen was already set up
locations for Type III hs
The sites of involvement can be systemic or localized. Blood vessels, as well as organs where blood is filtered to form other fluids, such as kidneys and synovium, are common sites of injury. Thus patients may develop symptoms related to vasculitis, glomerulonephritis, and arthritis.
Key steps in immune-complex mediated hs
Immune complex formation
Immune complex deposition
Immune complex-mediated inflammation and tissue injury.
Low levels of C3 indicate
active disease (type III hs) because complement is consumed as part of pathogenic process
levels of what can be used to measure immune-complex mediated disease
C3
examples of type III hs
SLE, poststreptococcal glomerulonephritis, polyarteritis nodosa, reactive arthritis, serum sickness, arthus reaction
type Iv cause by
Caused by inflammation resulting from cytokines produced by CD4+ T lymphocytes and cell killing by CD8+ T lymphocytes (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.
2 mechanisms of T cell mediated (type 4) hs
CD4+ T cell-mediated inflammation
CD8+ T cell-mediated cytotoxicity
CD4+ T Cell mediated inflammation
Repeat exposure of antigen, CD4+ T cells secrete cytokines –> recruit and activate macrophages and neutrophils –> tissue injury
examples CD4+ T cell mediated inflammation
delayed-type hypersensitivity (tissue reaction to antigens given to immune individuals)
Antigen given into skin of previously immunized individual –> detectable skin reaction w/in 24-48 hours
ie. Mantoux
CD8+ T cell mediated cytotoxicity
CD8+ cytotoxic T cells kill antigen-expressing target cells.
examples of CD4+ cytokine mediated inflammation
mantoux, contact dermatitis, MS, IBD
Examples of CD8+ cytotoxic killing
DM I and graft rejection
alternative to the mantoux
quantaferon: look at the cytokines - take cells, expose to TB - look for cytokines
granuloma trying to, activates what
It is a cellular attempt to contain an offending agent which is difficult to eradicate. Typically there is strong activation of T lymphocytes, leading to activated macrophages, resulting in tissue injury.
granulomas contain
A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelial-like cells (called histiocytes), with variable numbers of lymphocytes and plasma cells. The epithelial-like cells (histiocytes) may also fuse to form multi-nucleated giant cells.
foreign body granulas
see foreign material within histiocytes/giant cells, sometimes called “foreign body giant cell reaction” by pathologists
caseating granuloma
granulomas that induce cell mediated immune response with central necrosis; these are usually associated with infection (e.g. mycobacterial, fungal infections)
non-caseating granulomas
: granulomas that induce cell mediated immune response without central necrosis (e.g. Sarcoidosis, Crohn’s disease)
