Module 9 Flashcards
Clinical Applications of Immunology
hypersensitivity reactions
a detrimental effect of the immune system
- a reaction is termed hypersensitive either because it is a heightened or inappropriate response to an antigen
Gell-Coombs classification of immune injury
this system categorizes hypersensitivity reactions into 4 types: Type I, II, III, and IV
Type I hypersensitivity
Type I immediate hypersensitivity reactions can develop into anaphylactic responses
- type I is a specific antibody mediated reaction
- IgE on the surface of mast cells binds an allergen, resulting in mast cell degranulation
- some of the complement reaction byproducts (C3a, C4a, and C5a) can also cause this type of reaction
type II hypersensitivity
mediated by antibody directed against cell surface antigens
- AKA cytotoxic or costimulatory hypersensitivity
Type II reactions result in complement mediated lysis or cytotoxic action by NK cells
type III hypersensitivity
mediated by Ab-Ag immune complex deposited on the tissue
these immune complexes can activate complement and recruit innate immune cells to cause tissue damage
type IV hypersensitivity reactions
involve a complex interaction of T cells and monocytes/macrophages
- called delayed hypersensitivity (DHT) reactions
immediate/anaphylactic hypersensitivity
a type I reaction is an immediate response to an allergen
- most of these allergens are enzymes or glycoproteins.
- typical allergens include Fel d1 and Fel d4, Fra a1, der p1
sensitization
may occur via many routes including oral ingestion, respiratory inhalation, skin absorption, and IV
- the reaction is a result of IgE-mediated mast cell degranulation and are T cell dependent
type I hypersensitivity mechanism
- APCs present the processed allergen to Th2 cells. activated Th2 cells secrete IL-4 and IL-13, which induce naive B cells to undergo class switching from IgM to IgG2 to IgE secreting B cells
- secreted IgE binds to the F c-epsilon receptor on mast cells. the allergen cross-links two IgE antibodies bound to mast cells, resulting in mast cell degranulation
- mast cell degranulation results in the release of mediators, including vasoactive amines, which elicit biological effects within minutes
type I: mast cell activation
activated mast cells released pre-formed molecules and synthesize new vasoactive amines, leading to both early and late phase biological effects
early phase biological effects
immediate biological effects on mast cell activation are the result of the release of pre-formed molecules, such as:
- histamine, which promotes vascular permeability and smooth muscle contraction
- eosinophil chemotactic factor, which attracts eosinophils
- neutrophil chemotactic factor, which attracts polymorphic nuclear cells such as mast cells, eosinophils, and neutrophils
- proteases, which increase mucus secretion and causes basement membrane damage, especially in lungs
late phase biological effects
these are the result of synthesis of new vasoactive amines such as:
- platelet activating factor, which promotes aggregation of platelets, further mast cell degranulation, and smooth muscle contraction
- leukotrienes, which promote smooth muscle contraction and increase vascular permeability
- prostaglandins which promote smooth muscle contraction and vasodilation
- Bradykinin: promotes smooth muscle contraction and vascular permeability; involved in many pain pathways
effects of type I hypersensitivity
mediators released by mast cells effect:
- Blood Vessels: vasodilation and increased permeability result in edema. this loss of fluid in tissues can lead to anaphylactic shock
- Skin: vasodilation and edema can result in urticaria or eczema
- Nose and Eyes: vasodilation and increased permeability result in edema, which can manifest as rhinitis and conjunctivitis
clinical examples of Type I hypersensitivity
atopy: a predisposition to developing an allergic reaction
asthma: a condition where airways narrow and swell
laryngeal edema: a condition characterized by swelling of the larynx
atopy
an exaggerated IgE-mediated immune response to an environmental allergen - an inherited condition with genetic association to HLA, and can lead to asthma, atopic dermatitis, and allergic rhinitis
asthma
a respiratory condition characterized by increase in mucus secretion, edema, and contractions of brochiolar smooth muscle
- inflammation and obstructed airways are characteristic of an asthmatic reaction
key pathological components of asthma
increased recruitment of inflammatory cells
increased recruitment of mast cells, leading to high levels of histamine
- asthma can be atopic (reaction occurs in part of body not in contact with allergen), which is mediated by systemic IgE production, or non-atopic (reaction occurs in part of body in contact with allergen), which is mediated by localized IgE production, and does not occur in response to an allergen
laryngeal edema
a life-threatening swelling of the larynx characterized by inspiratory stridor (high pitched breathing sound)
allergy diagnosis
a common diagnostic test for immediate hypersensitivity reactions are skin prick tests, which measure the presence of IgE antibodies against suspected and common allergens. a positive reaction occurs within 1-20 minutes and will manifest as a small, red swelling
- this is a diagnostic test for a typical allergen
type II: cytotoxic/co-stimulatory hypersensitivity
these reactions involve antibody-mediated destruction of cells presenting allergens on their surface
- in this reaction, antigen-specific antibodies bind to the cell surface antigen and destroy the cell
- type II reactions are implicated in autoimmune diseases where the cells targeted are the host’s own RBCs
cell death
can occur by one of three mechanisms:
1. complement mediated cell lysis
2. phagocytosis
3. antibody-dependent cell mediated cytotoxicity (ADCC)
type II reaction mechanism: ADCC
antigen-specific antibody binds to the antigen via the Fab region
- specifically, cytotoxic cells have the CD16 gene, which binds to the Fc region of the antibody
- this cross linking between the target cell and the cytotoxic cell promotes cell killing due to the release of hydrolytic and digestive enzymes from the cytotoxic cells to the surface of the target cell
- the antibody does not directly kill target cells, but mediates cell death by presenting antigen cytotoxic cells
type II reaction: phagocytosis
antigen specific antibodies bind to the cell surface antigen via the Fab region. phagocytic cells have Fc receptors that bind to the Fc region of the antibody, cross-linking the antigen with phagocyte cells to enhance the process of phagocytosis
- if complement is activated, it promotes C3b on the surface of the target cell that can bind to the C3b receptor on phagocytes for enhanced phagocytosis
type II reaction: complement mediated lysis of target cell
antibody binding to antigen presented on the cell surface forms an Ab-Ag complex that activates the complement system, ultimately ending in cell lysis through a MAC attack
clinical examples of Type II reactions
hemolytic anemia: a condition where the immune system recognizes its own RBCs as foreign
Bullous pemphigus: autoimmune disease resulting in formation of blisters in the space between dermis and epidermis
Transfusion reactions: adverse reactions to allogeneic RBCs following blood transfusion reactions
Rh disease: a hemolytic condition in which the mother and fetal blood are incompatible
autoimmune hemolytic anemia
a group of blood disorders characterized by fatigue, dyspnea, and pallor. this is a result of lysis of RBCs due to antibodies
- lysis of RBCs consequently decreases the number of oxygen carrying blood cells in circulation
immune cells attack both self-RBCs and allogeneic RBCs that come from outside the individual, such as those from a blood transfusion
hemolytic disease
newborn disease which develops when maternal IgG antibody specific to the Rh-D allele crosses the placenta and destroys fetal RBCs by binding to Rh-D and activating complement
- can be fatal to fetus, but treated with intrauterine blood exchange transfusion
hemolytic disease is prevented by the use of anti-Rh antibodies
type III: immune complex hypersensitivity
these reactions are mediated by immune complexes deposited in the tissue
- these complexes can damage various tissues, primarily through complement activation and recruitment of innate immune cells
type III inflammatory diseases
vasculitis
carditis
synovitis
dermatitis
glomerulonephritis
size of type III immune complex
depends on the ratio of antigen:antibody present
- this has implications on the immunogenicity of the complex
type III mechanism
- antigen:antibody complexes deposit in tissue or blood vessel wall
- immune complexes activate complement components and attract inflammatory cells
- vasoactive amines (histamine) released by basophils will increase the vascularity of the tissue
- prolonged complement activation results in tissue damage due to enzymes released by neutrophils
type III diagnostic application
the Arthus reaction is the skin test that detects an excess of local antibodies
- the reaction involves in situ formation of immune complexes after intradermal injection with an antigen
- if a patient has previously been exposed to the antigen and has circulation antibody, an Arthus reaction will occur
arthus reaction
not an immediate reaction and generally develops over 6-12 hours if antibody levels are elevated in circulation
clinical presentation of type III hypersensitivity
- serum sickness: reaction to proteins in antiserum derived from non-human animals
- Farmer’s lung: hypersensitivity pneumonitis - rheumatoid arthritis: a long term autoimmune disorder involving both Type II and III hypersensitivity
serum sickness
a reaction to proteins from an animal source which arises from the introduction of certain non-protein substances or following vaccine administration
- the immune system reacts to the foreign antiserum proteins by producing specific antibodies and forming immune complexes, which enter the blood vessels and activate complement cascade
- complement reaction results in hypocomplementemia and fatigue
Farmer’s lung
induced by exposure to dust and mold spores found in hay
- occurs when inhaled antigens cause Ig-mediated immune complexes to form in the alveoli. complexes cause fluid, protein, and cells to accumulate in the alveolar wall, compromising the blood-gas exchange in the lungs
- after multiple exposures, it takes fewer antigens to elicit a reaction
farmer’s lung symptoms
results in fever, chills, and chest pain due to the local reaction in the lungs and occurs about 6-8 hours after exposure
rheumatoid arthritis
an autoimmune disorder that affects the joints
- the body’s immune system attacks the joints, resulting in inflammation and thickening of the joint capsule
- rheumatoid factor is an IgG or IgM antibody that binds to IgG in synovial joints. the immune complexes deposit in the joints causing injury to articular cartilage
type IV: delayed hypersensitivity
AKA DTH
reaction requires days to develop, occurs over 48-72 hours
this type of reaction is cell mediated and is initiated by sensitized helper T cells
characterized by the recruitment of activated macrophages at the site of the reaction
initiation of DTH
requires sensitization by an antigen
- these steps involve uptake, processing, and presentation of the antigen by local APCs. initial exposure of an allergen triggers production of a CD4+ Th1 cell response. this sensitization reactions evolves over a 1-2 week period of time
effector phase of DTH
the effector phase is induced by a secondary exposure to a sensitizing antigen. Th1 cells enter the sire of antigen presentation, recognizing peptide:MHC Class II complexes on APCs, and release inflammatory cytokines
- cytokines stimulate expression of adhesion molecules on the endothelium to increase local blood vessel permeability to allow macrophages and other cells to enter the site
DTH aggregation of cells
a prolonged inability to clear antigens can result in aggregation of cells
- characteristic skin lesions appear 24 hours after, reaching their peak 48-72 hours after second exposure
DTH diagnostic application
DTH reaction can be detected using a skin test. a small amount of sensitizing agent is injected under the skin
- if a red, slightly swollen, firm lesion develops within 48-72 hours, the test is positive, indicating that the individual has a population of sensitized Th1 cells against the pre-exposed antigen
- this does NOT indicate an active infection or if the individual has overcome an infection
type IV clinical effects
DTH: causes local skin swelling, dermatitis
contact hypersensitivity: caused by hapten antigens, causes local epidermal reactions
celiac disease: antigen is giladen, causes atrophy in small bowel
contact dermatitis
type IV reaction where sensitization can occur if a reactive chemical compound binds to the skin proteins, and the modified proteins are then presented to T cells. these can be induced by: poison ivy, oak, nickel, cosmetics
reactions cause strong cell-mediated responses against skin cells, including blisters and rashes
immune mediators of each reactions
I: IgE
II: IgG or IgM
III: immune complexes deposited on tissue
IV: T-cells
autoimmune disease
AI diseases are the result of over-reactivity of the immune system against its own tissues
- the presence of anti-self antibodies or anti-self mediated immunity will not necessarily develop into an autoimmune disease
AI diseases can be organ specific or systemic, and affect 5-7% of the population. some AI diseases have been linked to certain MHC haplotypes as they could fail to delete anti-self T and B cells
central tolerance
mechanism by which the immune system learns to discriminate self from non-self antigens
- lymphocytes with receptors to self antigens are removed with apoptosis
peripheral tolerance
mechanism by which the body prevents over-reactivity of the immune system to various environmental factors such as allergens and microbes
defects in tolerance
can cause AI disease as lymphocytes specific to self antigen or some environmental factors remain in circulation
AI disease and the MHC
MHC class II presentation of self or foreign peptides to T cells can result in immunological tolerance.
due to the role of MHC in antigen presentation, some HLA genes have been associated with AI diseases
- individuals with these HLA genes have an increased relative risk for these diseases
intrinsic factors to AI susceptibility
inheritance of AI diseases can be determined clinically by HLA typing
- individuals with these genes are said to be at very high relative risks (RR) for developing the disease
HLA associated diseses
insulin dependent diabetes: HLA DR3 haplotype makes it 100x more likely to result in insulin dependent diabetes
ankylosing spondylitis: type of arthritis that affects the spine (vertebrae fuse together, causing rigid spine) HLA B27 haplotype expression makes it 90x more likely to develop
mechanisms of autoimmune disease
anti-self B and T cells in circulation need to be triggered to become activated
there are 3 major mechanisms for triggering these cells:
1. molecular mimicry
2. release of sequestered antigen
3. polyclonal B cell activation
molecular mimicry
foreign antigens can have epitopes that are similar to those of self-antigens
- as a result, immune response against a foreign antigen may result in cross activation of the anti-self cells, causing damage to self tissues expressing similar epitopes
since the foreign antigen has similar epitopes to the self antigen, the immune response will attack both
molecular mimicry in AI diseases
streptococcus bacteria display similar epitopes to those expressed in heart muscle
- molecular mimicry results in rheumatic carditis after infection
- characterized by cardiac inflammation and scarring as a result of cross-reactivity of antibodies due to molecular mimicry
diseases caused by antigen mimicry
MS: bacteria that cause MS include Epstein-Barr virus, human herpesvirus 6
Ankylosing spondylitis: antibodies against Klebsiella can cross react with HLA B27
sequestered antigen
self antigens in immunologically privileged sites (brain, eye lens, heart muscle) are sequestered from the immune system
- this is because these self antigens were not presented to developing lymphocytes during maturation, and therefore there was no development of tolerance to these antigens
trauma and sequestered antigens
in the event of infection or trauma, these sequestered antigens can become exposed to the immune system, which may result in the newly exposed antigens being recognized as foreign, initiating an AI disease
clinical example of sequestered antigen
sympathetic uveitis is inflammation that occurs following accidental insult to the eye
- these cells have never been exposed to the immune system, therefore when they are exposed because of injury, the body produced antibodies against them (anti-self)
polyclonal B cell activation
EBV and CMV viruses can activate mature B cells to produce antibodies with different specificities
- the production of a wide range of antibody specificities as a result of infection causes a greater chance of cross-reaction to different antigens, including different bacteria and self antigens
- Anti-DNA and anti-RBC antibodies can result in the development of AI
clinical example of polyclonal B cell activation
EBV virus causes mono, and infection is transferred through saliva and genital secretions to inject epithelial cells of the oropharynx
- persistent EBV infection can shift between an active lytic cycle and a latent state enabling evasion of the immune system and allows for the initiation of AI disease
types of AI diseases
AI diseases can be organ specific or systemic
- organ specific AI involve an immune response against self-antigens in a single organ (ex: Grave’s disease or diabetes)
- systemic immune response is self-antigens throughout many different tissues (ex: arthritis)
organ specific: myasthenia gravis
a chronic autoimmune disease that results from antibodies against ACh receptors at the neuromuscular junction, preventing muscle contractions
- under normal conditions, ACh released from the pre-synaptic nerve binds to AChR on the post-synaptic neuron. AChE degrades excess ACh
- with AI, antibodies against AChR prevent ACh binding. this is treated with AChE inhibitors that inhibit AChE degradation of ACh. a higher concentration of ACh increases the likelihood of binding
myasthenia gravis treatment
patients will experience muscle weakness as a result of antibodies against AChR at the neuromuscular junction. drooping eyelids is characteristic of this disease
- significant improvement is noticeable following AChE inhibitors treatment
organ specific: Grave’s disease
AI disease that manifests as hyperthyroidism, as a result of antibodies against the TSH receptor
- in Grave’s disease, antibodies against TSH receptor cause chronic activation, producing abnormally high T3 and T4 levels
Grave’s disease symptoms
bulging eyes
goitre
muscle weakness
organ specific AI: Goodpasture’s syndrome
AI disorder where antibodies attack the basement membrane of the lung alveoli and glomerulus in kidney
- circulating anti-GBM antibodies bind to epitopes on the basement membrane and activate a complement cascade, leading to bleeding from the lungs and kidney failure
systemic: systemic lupus erythematosus
the body makes anti-nuclear and anti-cytoplasmic antibodies
- immune complexes are deposited in different tissues, ultimately triggering inflammation that results in conditions such as arthritis, carditis, and dermatitis
systemic: rheumatoid arthritis
AI disease that primarily affects the joints. mediated by T cells and/or antibodies
rheumatoid arthritis: T cells
Th1 cells engage with a specific antigen in the joints, and they release cytokines that initiate local inflammation
- leukocyte recruitment causes damage to the cartilage in the joint leading to its destruction
arthritis: antibodies
RA involves IgM anti-IgG autoantibody (RF factor) which deposit in joints and blood vessels and are associated with destructive inflammation
primary immunodeficiency
caused by hereditary or genetic defects that result in the absence or improper functioning of parts of the body’s immune system
- AI diseases of this type share a common factor of causing a defect in one of the body’s immune system functions, either by affecting one component or multiple components of the immune system
primary immunodeficiency classifications
classified based on which part of the immune system is affected
- humoral immunity (B-cells)
- cellular immunity (T-cells)
- humoral and cellular immunity (B and T cells)
the affected component of the immune system can be missing, reduced in number, or abnormal, and malfunctioning, immunodeficiencies involving problems with B cells account for more than half the primary immunodeficiency disorders
digeorge syndrome: T cell deficiency
primary immunodeficiency that is the result of a deletion of a segment of chromosome 22
- causes developmental thymic aplasia, in which the thymus fails to develop, where T cells are supposed to mature.
- this causes the absence of of cell mediated immunity due to lack of differentiated or immune T cells
- patients have an increased susceptibility to fungal and viral infections
Bruton’s agammaglobulinema
inherited immunodeficiency disease caused by mutations in the gene coding for BTK, which is responsible for mediating B cell development
- individuals do not generate mature B cells, resulting in a lack of Ig in the bloodstream. individuals are prone to serious and fatal bacterial infections
treating Bruton’s
XLA is typically treated by IV infusion of antibodies
- does not cure XLA, but reduces severity of infections due to passive immunity
SCID
a group of defects from one of many genes that results in a heterogenous disorder
- defective genes play a role in the proper development of B and T cells, and SCID causes a defective antibody response either directly through mature B cell malfunctioning, or indirectly through ineffective T cell dependent B cell activation
- SCID causes affected individuals to be highly susceptible to life threatening infections by viruses, bacteria, and fungi
- infected individuals must live in a sterile environment
mechanisms of SCID development
most cases of SCID are X lined, due to mutations in the gene that codes for the common gamma chain on the X chromosome
- mutations prevent the development of a fully functional immune system due to low T cell and NK cell count, and non-functional B cells
- receptors for certain cytokines are not functional and cannot exert their effects
acquired immunodeficiency
not genetic, but caused by external factors
four main causes: malnutrition, medication, aging, and disease
malnutrition
deficiency in one or more nutrients can result in the improper functioning of the immune system
- mainly caused by protein calorie deficiency, where the T cell population decreases in proportion to protein levels
medication immunodeficiency
cytotoxic agents such as chemotherapy and radiation therapy target rapidly dividing cells in the body, but this effect can suppress the immune system
aging: immunodeficiency
the thymus shrinks as you age, and the thymus produces fewer T cells that can respond to antigens
- micronutrient malnutrition is a particular concern for aging population as it impairs the immune system
- calcium and zinc are common deficiencies in the elderly
disease: immunodeficiency
prolonged or chronic disorders can result in secondary immunodeficiency due to stress placed on immune system
HIV
most common secondary immunodeficiency, transmitted through bodily fluids
- HIV interacts with CD4 and CCR5 receptors
- viral reverse transcriptase copies RNA genome of HIV and integrates it into host genome
effects of HIV
direct viral effect on infected cells as the budding process of the virus destroys the membrane of the infected cells
- additionally, cells die from apoptosis induced by over-expression of antigenic ligands
- accelerated apoptosis accounts for the low CD4+ T-cell counts
consequences of HIV
loss of CD4+ helper T cells contributes to the abnormal production of IL-1 and TNF-a
- collectively, this leads to decreased proliferation in response to antigens, decreasing DHT and cell mediated immunity against infections
immunological abnormalities of HIV
abnormal macrophage function (IL-1)
decreased NK cell activity
decreased CD8+ cytotoxic T cells
increased non-specific Ig
increased auto-antibodies
idiopathic immunodeficiencies
diseases that have an unknown cause
- most commonly B cell immunodeficiencies
- includes CVID (defects in the antibody variable region) and selective IgA deficiency (foreign IgA elicits an immune response)
