Hypersensitivity reactions Flashcards
Introduction to hypersensitivity
Injurious or pathogenic, immune reactions are called hypersensitivity reactions
Same mechanisms as the normal response
-too intense
-directed against Ag that post no threat
-taking place at inappropriate locations
Originally classified in 4 types based on the principal immunologic mechanism that is responsible for tissue injury and disease
Type I hypersensitivity
Allergy or atopy
Type I hypersensitive cause antigen-allergen
no one knows for sure what drives type 1
Tendancy to develop allergies might be regulated by the intestinal microflora
Developed countries increase incidence of allergies
-changes in diet?
-use of antibiotics?
Type I hypersensitivity
- exaggerated Th2 response
- Overproduction of IL-4
- Excessive production of IgE
- IgE binds to Mast Cells
- Contact with allergen
- Mast cell degranulation
Key elements in excessive IgE production
Predisposed to generate Th2 cells
-IL-4 (produced in significant amount of mast cells), IL-5 and IL-13
leads to IgE synthesis
IgE receptors
FceRI -very high affinity -almost irreversible -2 forms -Found on mast cells, basophils, neutrophils, eosinophils FceRII (CD23) -low affinity
Overproduced IgE will bind to to mast cells and stay for a long time
People with allergies will respond quickly
Mast cells
Connective tissue, under mucosal surfaces and around nerves
Greater numbers skin, intestine and airways
Key role in inflammation
Several PRRs
-TLRs1, 2, 3, 4, 6, 7, 9 and a mannose receptor (CD48)
activators of innate immune response
Mast cell degranulation
Degranulation is quick
Effects of mast cell degranulation
Vascular dilation, smooth muscle contration Tissue damage vascular dilation Smooth muscle contraction Inflammation (leukocyte recruitment)
Interleukin 33 (IL-33)
Important role in inflammation
Promotes Th2 responses leading to allergies
Smooth muscle cells, epithelial cells, fibroblasts keratinocytes, dendritic cells, and activated macrophages
Induces mast cell degranulation in the presence of IgE
Clinical Type I hypersensitivity
Allergic anaphylaxis
- life-threatening systemic hypersensitivity reaction
- clinical presentation varies according with the species
- Generalized mast cell degranulation and massive mediator release
Specific allergic disorders
Food allergies Atopic dermatitis Allergies to parasites Allergies to drugs Eosinophilic granuloma complex Milk allergy
Atopic dermatitis
A genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features. It is most commonly associated with IgE antibodies to environmental allergens
Chronic, multifactorial syndrome characterized by chronically inflamed and itchy skin
Common in dogs: retrievers, setters, terriers, etc
Recognized in cats, horses, and goats
Food allergies
Not the same as intolerance -> not immune-mediated
Only 10-30% will manifest GI problems from mild to severe
Most cases lead to skin problems (related to AD?)
Diagnosis of Type I hypersensitivity
Intradermal testing- usually preferred Passive Cutaneous Anaphylaxis (PCA) Measurement of IgR levels -ELISA, Western Blotting -low specificity
Type II hypersensitivity
Antibody-dependent cytotoxicity or cytotoxic hypersensitivity
Antibody recognizes antigen on cell surface
-complement-mediated or cell-mediated cytotoxicity
Mediated by IgG and IgM
Opsonization and phagocytosis
Complement and Fc receptor-mediated inflammation
Abnormal physiologic responses without cell/tissue injury
Incompatible blood transfusions
- Recipient carries antibodies for blood group antigens expressed on the donor RBCs
- Depending on the species: Ab without previous exposure
Hemolytic disease of the newborn (HDN) neonatal isoerythrolysis
Relatively common in foals
More common in mules than horses
-8-10% vs 0.05-2% respectively
Mare is sensitized against fatal RBC antigens
-Transplacental hemorrhages over repeated pregnancies
-Aa (EEA system) is most severe
-Qa (EAQ system) -> slower onset
Aa and Qa -> 90% of casesBovine Neonatal Pancytopenia
Vaccine induced alloimmune disease
Highly adjuvanted bovine virus diarrhea vaccine (BVD)
-inactivated cytopathagenic BVDV grown on bovne kidney cells
-high levels of anti-mhc alloantibodies in cattle
-Transferred to calves via colostrum bind to leukocytes and bone marrow stem cells
-Presentation of disease is dependent on inheritance from the father
Type II hypersensitivity reactions to drugs
Certain drugs can be absorbed onto cell surface glycoproteins.
- Penicillin, quinine, L-dopa, aminosalicylic acid and phenacetin RBCs
- Sulfonamides, phenylbutazone, aminopyrine, phenothiazine and chlororamphenicol- granulocytes
- Phenylbutazone, quinine, chloramphenicol and sulfonamides-Platelets
Type II hypersensitivity Reactions
Infectious Diseases
- Bacterial LPS
- Equine infectious anemia virus
- Babesia
- Anaplasma
- Hemotropic mycoplasmas
Autoimmune type II hypersensitivity reactions
Type III hypersensitivity
Immune complex mediated
- formed with IgG and IgM
- severity determined by amount of immune complexes and site of deposition
- local reactions: complexes within tissues
- Systemic reactions: complexes formed in bloodstream
The antibody will form a complex with an antigen and/or a complement. This will bind to CR1 on erythrocytes. Kupffer cells will take the immune complexes off by phagocytosis and the erythrocyte will be recycles. If there are too many complexes being made for how fast the body can clear them than this mechanism will not be enough
Accumulation of complexes in a specific site can lead to severe scenarios
Can lead to platelet aggregation; macrophage activation; release of proteolytic enzymes and polycatonic proteins; release of histamine, prostaglandins, leukotrienes etc
Arthus reaction
Localized type III hypersensitivity reaction caused by the subcutaneous injection of an antigen on previously sensitized animal
Induces immune complex-mediated vasculitis with local necrosis (just at the injection site)
Antigen in tissues and antibody form immune complexes. This activated macrophages, neutrophils, complement, and mast cell degranulation. All eventually leads to tissue destruction (via inflammatory mechanism)
Local type III hypersensitivity: Blue eye in Dogs
Canine adenovirus Type I (infection or live vaccine)
Anterior uveitis leading to corneal edema and opacity
The cornea is infiltrated by neutrophils and virus-antibody complexes are present in the lesion.
Local type III hypersensitivity: Hypersensitivity Pneumonitis
When sensitized animals inhale antigens
Thermophilic actinomycetes in hay
-saccharopolyspora rectivirgula-small spores that can be inhaled
-acute alveolitis, vasculitis and exudation of fluid into the alveolar spaces
Equine respiratory disease (RAO & IAD)
-probably Th2 response
-no evidence of IgE involvement
Local type III hypersensitivity: Staphylococcal hypersensitivity
Pruritic pustular dermatitis of dogs
Skin testing suggests that types I, III, and IV hypersensitivity may be involved
The histological findings suggest that the type III reaction may predominate
Serum Sickness
Generalized type III hypersensitivity
Observed as a reaction to treatment for diphtheria with hyperimmune serum obtained from horses
Arthritis, fever, rash
Initially thought to be caused by proteins in the serum
Soluble complexes deposited in vessel walls
Causes arteritis, glomerulonephritis, arthritis
Glomerulonephritis
Type I, II and III membranoproliferative glomerulonephritis
small immune complexes can go to the epithelial cell from the blood- epithelial cell proliferation
large complexes stay in the blood or attache to the basement membrane-mesangial and endothelial cell proliferation
Type IV hypersensitivity
Delayed hypersensitivity Mediated by T cells- no need for Ig -unlike antibodies (preformed), needs time to proliferate and secrete cytokines 12 hours-inflammation 24-72 hours-maximum intensity
Cellular mechanism of Type IV hypersensitivity
Cytokine mediated inflammation
- INF-y and IL-17
- Macrophage and neutrophil recruitment
- Tissue APC with CD4+ T cell releases cytokines. Causes inflammation, neutrophil enzymes and ROS that lead to tissue injury
CD8+ killing of host cells
Antigen injected, langerhans cells, afferent lymph, draining lymph nodes, to blood, sensitized T cells, lymphotactin, IL1 TNFa etc, macrophages inflamation
Pathological consequences of Type IV hypersensitivity: granuloma formation
Granuloma formation
- mycobacterium is resistant to intracellular destruction and very slowly removed (M1)
- ingest the bacteria but fail to prevent its growth
- multinucleated giant cells
- lesion that develops around the caseous necrotic center
- surrounded by a layer of fibroblasts, lymphocytes, and macrophages (epithelioid cells)
- Low pH and lack of oxygen-bacteria unable to multiply survive in a dormant state
- adequate response (Th1)- may control the infection
- Inadequate response (Th2)-organisms escape and spread to local lymph nodes and nearby tissues
- virulent bacteria exploit tissues repairing by macrophages
Pathological consequences of Type IV hypersensitivity: Allergic contact dermatitis
Epidermal route of inoculation
Foreign low- molecular weight materials capable of binding to peptides within the groove of MHC molecules on the surface of Langerhans cells
IL-12, IL-18, and IL-23 -> Th1 and Th17 cells
Th1 -> IFN-y
-promote the activities of cytotoxic T cells
Highly reactive molecules
Combine with skin proteins to act as haptens
-formaldehyde, plant resins, nickel etc.
Mascular papular dermatits
Tends to be confined to hairless or sparsely haired areas of skin in contact regions
-ventral aspect of interdigital areas, ventral abdomen and thorax, ventral tail and neck, scrotum and perineal area, muzzle, and concave aspect of pinnae.
