Home > Preview
The flashcards below were created by user
on FreezingBlue Flashcards.
Human MHC molecules
- MHC I - HLA-A, B, C
- MHC II - HLA-DP, DQ, DR
- The adaptive immune response sometimes mounts an immune response against normally harmless antigens.
- Classified into four types by Coombs & Gell, according to speed of reaction and the immune mechanism involved.
Classification of Hypersensitivity Reactions
- Type I - IgE mediated, mast cell degranulation
- Type II - Ab (IgG, IgM) mediated, may involve complement, ADCC, etc
- Type III - immune complex deposit (IgM, IgG, antigen)
- Type IV - CD4/8 T cell mediated, inflammation, phagocytosis, cytolysis
Originally meant altered reaction because an individual has been previously exposed to an antigen, and has become _____ to the innocuous antigen (“_____”).
The responses are characterized as ________.
Refers to Type __ hypersensitivity reactions. They are the commonest of the hypersensitivity reactions.
- allergic reactions
Allergen - Many routes
- skin contact
- blood, systemic - Quick, anaphylaxis
Antigen binding to IgE on mast cells or basophils leads to amplification of IgE production
Mast cell-IgE binds allergen, signal to produces IL-4, which causes the B cell to switch its class, produce more IgE
Enzymatic activity of some allergens enable penetration of epithelial barriers
- Der p 1 (from dust mite feces) cleaves tight juction, penetrates mucosa
- DC captures it, presents it, induces TH2
- TH2 induces B cell to form IgE producing plasma cell
- plasma cell migrate to mucosa, secrete IgE
- IgE binds to mast cell, activates it when binds to Der p 1
- active mast cell degranulates and causes allergic symptoms
The Hygiene Hypothesis
- Early Childhood in unclean environment – Th1 responses as adults; nonatopic
- Early Childhood in clean environment – Th2 responses as adults; atopic
exaggerated IgE responses to common environmental antigens. This is called _____.
- when the allergen is introduces directly into the Bloodstream, or is rapidly absorbed from the gut.
- Connective tissue mast cells become activated - Widespread vascular permeability leading to drastic loss of blood pressure, difficulty breathing, swelling of the epiglottis & can cause suffocation.
- The potentially fatal syndrome is called anaphylactic shock
The wheal and flare reaction in the skin
- induced by intradermal injection of Ag
- wheal before flare
Passive cutaneous anaphylaxis (PCA) test
- Zoltan Ovary 1964, guinea pig
- An assay for Ag-specific IgE, in which an animal is sensitized to by subcutaneous injection of test serum and then challenged with allergen. If specific IgE is present in the serum, local mast cells degranulate, causing vascular permeability
The Prick test:
Is used to detect type I hypersensitivity to allergens- wheal And flare response
Allergic Diseases in Humans
- Systemic anaphylaxis
- Bronchial asthma
- – Intermittent & reversible airway obstruction
- – Chronic bronchial inflammation with eosinophil infiltration
- – Bronchial smooth muscle hypertrophy and hyperreactivity
- Allergic rhinitis (hay fever)
- Food allergies
- Urticaria and eczema
Allergic responses in the oral cavity
- Medications - penicillin, sulfa drugs
- Dental materials - restorative metals, acrylic denture materials, dental impression materials, denture adhesive materials
- Latex gloves
Approaches to treatment of allergy
- Corticosteroids -> General anti-inflammatory effects
- Desensitization therapy by injections of specific antigen -> Induction of regulatory T cells
- Anti-lgE antibodies (omalizumab) -> Bind to lgE Fc region and prevent lgE binding to Fc receptors on mast cells
Type II Hypersensitivity
- Caused by IgG or IgM Abs against cell surface extracellular matrix Ags. Tissue damage is caused by complement activation, and by binding and activating effector cells carrying Fcγ receptors, eg neutrophils and macrophages.
- May target cells: transfusion reactions to erythrocytes, produced by blood group Ags, which may occur naturally or may be induced by previous contact with incompatible tissue or blood following transplantation, transfusion or during pregnancy
- Hemolytic disease of the new born occurs when
- maternal Abs cross the placenta and destroy fetal RBC.
- May target tissues: Ab binds to functional receptors to inhibit or enhance their activity.
Neutrophil-mediated type II damage
- neutrophil adherence - instead of attach to microbes, it attach to basement membrane
- frustrated phagocytosis
- extracellular enzyme release
ACh receptor deficiency due to anti-receptor Ab
Type II Hypersensitivity reactions may target blood cells (usually, but not always erythrocytes)
ABO and Rhesus Ags are strong immunogens
Transfusion of allogeneic erythrocytes into an individual who already has Abs against them may produce erythrocyte destruction and symptoms of transfusion reaction.
Hemolytic disease of the new born
- First birth - fetus Erythrocytes of RhD+ leak into maternal circulation; Anti-RhD Ab are produce in mother (postpartum)
- Subsequent pregnancy - Anti-RhD Ab in Mother cross placenta to react with RhD+ fetus, resulting in erythrocyte destruction
- Anti-Rh Ab is injected immediately postpartum
- Mother doesn’t have a chance to make Ab to RhD
Other diseases caused by cell- or Tissue-Specific Ags
- Goodpasture's syndrome - target Noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli, leads to Nephritis, lung hemorrhage
- Autoimmune thrombocytopenic purpura - Platelet membrane proteins
- Insulin-resistant diabetes (Type II Diabetes) - Insulin receptor
Immune complexes normally bind _____ and are removed to ________ after binding _____ on _____.
- liver and spleen
- Normal process when the complex is small; happens constantly.
- Can also go via factor I - hepatic macrophages (Kupffer cells) route, other than RBC
Type III Hypersensitivity
- Ab-Ag Immune complexes
- normally removed by mononuclear phagocytic system, following complement activation.
- Persistence of immune complexes due to continued infection or autoimmune disease leads to immune complex disease
Immune complexes as trigger for _____.
In inflammation, immune complexes bind _______ to produce _______ (e.g. ______, _______), which cause _________ and, thus increase ___________.
- basophils and platelets
- vasoactive amines
- endothelial cell retraction
- vascular permeability
Deposition of immune complexes in vessel walls
- Immune complex is formed
- complements like C3 and C5 go to neutrophiles
- neutrophiles are called to the site
- degranulate, release enzymes that cause damage to the blood vessel
Three categories of immune complex diseases
Persistent infection, Autoimmunity, Inhaled Ag
Persistent infection, Autoimmunity, Inhaled Ag
- Microbial Ag -> Infected organ(s), kidney
- Self Ag -> Kidney, joint, arteries, skin
- Mold, plant, or animal Ag -> Lung
Immune complex disease is a frequent complication of ________
Immune complex disease: E.g.
- Rheumatoid arthritis – chronic inflammation of joints
- Systemic lupus erythematosus (SLE)
- Polymyositis – inflammation of muscle fibers
Human immune complex-mediated Diseases
SLE, polyarteritis nodosa, poststreptococcal glomerulonephritis, serum sickness
disease: antigen -> manifestations
- SLE: DNA, nucleoproteins -> nephritis, arthritis, vasculitis
- Polyarteritis nodosa: HBV surface Ag -> vasculitis
- Poststreptococcal glomerulonephritis: streptococcal cell wall Ag -> nephritis
- Serum sickness: proteins -> arthritis, vasculitis, nephritis
Systemic Lupus Erythematosis (SLE):
Believed to be due to abnormal ___________
Genetic predisposition – _________
More prevalent in _______
- clearance of apoptotic material from dying cells
- HLA DR2/DR3
Serum sickness- classic example of a transient immune complex-mediated syndrome (a type III hypersensitivity reaction)
- Foreign serum injection
- foreign serum proteins plasma level rise quickly, slowly decline until Ab level starts rising and symptoms begin
- foreign serum drops drastically to zero while Ab rises, immune complexes raises to the peak
- immune complexes drops quickly after the peak while Ab continues rising
- Ab rising rate slows down, and symptoms stop
- type III hypersensitivity reaction
- a local inflammatory response caused by the deposition of immune complexes in tissues
- Develops within 1-2 hrs
- - local injection of Ag in immune individual w/ IgG Ab
- - local immune-complex activates complement, C5a binds to and sensitizes the mast cell to respond
- - activation of FcγRIII on mast cells induces degranulation
- - local inflammation, increased fluid and protein release, phagocytosis, blood vessel occlusion
The pathology of type III reactions is determined by ___________.
the sites of immune complex deposition
Route: site of deposition - disease
- IV (high dose):
- blood vessel walls -> vasculitis
- renal glomeruli -> nephritis
- joint spaces -> arthritis
- perivascular area -> Arthus reaction
- Alveolar/capillary interface -> farmer's lung
- There can be different effects on the skin, eg. urticarial rash, skin hemorrhage
Type IV Hypersensitivity (DTH)
- Delayed type hypersensitivity
- Via CD4 T cells, particularly TH1, rather than by serum.
- can occur in Ab deficient humans; is lost with decline in CD4 T cells, eg. AIDS.
- presence of Ag-specific CD4 T cells, associated with protective immunity against intracellular and other pathogens.
- Ag: proteins - insect venom, Mycobacterial proteins (tuberculin, lepromin)
- Consequences: local skin swelling - erythema, induration, cellular infiltrate, dermatitis
- Ag: Haptens - pentadecacatechol (poison ivy), DNFB (dinitrofluorobenzene); metal ions - nickel, chromate
- Consequences: local epidermal reaction - erythema, cellular infiltrate, vesicles, intraepidermal abscesses
- Gluten-sensitive enteropathy
- Ag: gliadin
- Consequence: villous atrophy in small bowel, malabsorption
The stages of a delayed-type hypersensitivity reaction
- Takes 24-72 hrs
- Ag injected into subcutaneous tissue and processed by local APC - Priming T cell
- TH1 effector cell recognizes Ag and releases cytokines, which act on vascular endothelium - T cell action
- Recruitment of phagocytes and plasma to site, causes visible lesion - inflammation
Antigen-stimulated TH1 cells in the delayed-type (type IV) hypersensitivity release
- chemokines - cell recruiting
- IFN-gamma - induces vascular adhesion molecules; activates macrophages, increasing release of inflammatory mediators
- TNF-alpha and LT - destruct local tissue; increase expression of vascular adhesion molecules
- IL-3/GM-CSF (granulocyte monocyte-colony stimulating factor) - stims monocyte production by bone marrow stem cells
Elicitation of DTH response to a contact-sensitizing agent
- contact-sensitizing agent penetrates the skin and binds to self proteins, taken up by Langerhans
- Langerhans present self peptides haptenated w/ the contact-sensitizing agent to TH1, which secrete IFN-gamma, etc.
- Activated keratinocytes secrete cytokines such as IL-1 and TNF-alpha and chemokines such as CXCL8,11,&9.
- Above secretion and TH1 activate macrophages to secrete mediators of inflammation, such as IL-1, TNF-alpha, NO.
Contact hypersensitivity can be confirmed by ____.
patch test - positive reaction of localized area of eczema 2-4d post application
Haptens are _____________. Haptens are recognized by _______, which __________.
- small antigenic determinants which cannot, by themselves elicit an immune response, but would elicit response when hooked to a larger molecule (carrier)
- B cells
- present fragments of the carrier to T cells
- Dense dermal infiltration of leukocytes, 48-72 hrs
- after injection of leprosy bacillus.
Granulomatous hypersensitivity & the tuberculin skin reaction
- Responses induced by Ag-specific TH
- Disease - granuloma, contact hypersensitivity
- Diagnosis - contact hypersensitivity, tuberculin response
- - Chronic immune response to gluten proteins in wheat, oats and barley
- - severe inflammation of the intestinal (eg. jejunum) wall leading to loss of slender finger-like villi
- - increased T cells, macrophages, and plasma cells in the lamina propria
- - Strong genetic predisposition, HLA-DQ2/DQ8 Class II MHC allele
Molecular basis of immune recognition of gluten in celiac disease.
- - Gluten peptides normally don't bind to MHC II molecules
- - tTG modifies gluten peptides so they can bind to MHC II molecules
- - bound peptide activates gluten-specific CD4 T
- - activated T kills mucosal epithelial cell by binding Fas via FasL. T also secretes IFN-gamma to activate epithelial cells.
The activation of cytotoxic T cells by the innate immune system in celiac disease
- gluten peptides activate mucosal epithelial cells to express MIC molecules
- intraepithelial lymphocytes (IELs, CD8 T) express NKG2D, binds to MIC and activates the IELs to kill the epithelial cell
- IL1 and IL1R also involved
Immune activity hypothesis of celiac disease
- Ab against tissue transglutaminase (tTG) is found
- no T cells specific for tTG found
- gluten specific T cells are found
- Explanation: gluten can form complex w/ tTG, thus gluten specific T cells can activate anti-tTG Ab-producing B cells. (No evidence supports anti-tTG Ab further damages the tissue)
Diseases associated with Type 4 Granulomatous hypersensitivity
- Leprosy – Mycobacterium leprae
- Tuberculosis - Mycobacterium tuberculosis
- Schistosomiasis – Schistosoma mansoni (worm)
- Sarcoidosis – Inflammatory immune response (usually in lung); etiology is undefined
- Crohn’s disease – Inflammation of the GI tract (autoimmune), response to enteric bacteria
Appearance of the three main skin test reactions
- Type I hypersensitivity:
- Raised wheal (5-7 mm dia)
- 15 min
- Type III hypersensitivity:
- Arthus reaction (> 50 mm)
- 5-12 hours
- Type IV (delayed) hypersensitivity:
- tuberculin response
- 24-48 hours