31. immune mediated diseases part I (type I & II hypersensitivities)

examples of chronic type I hypersensitivities

• atopic dermatitis

• asthma

what body regions are typically affected in atopic dermatitis?

feet, face, ventrum

progression of atopic dermatitis

• genetic predisposition for T_H2 responses & IgE production

• allergen is introduced & elicits response

  • secretion of T_H2 cytokines → allergen-specific IgE production → IgE binds to mast cells/eosinophils → degranulation when IgE binds antigen

• chronic phase: pro-inflammatory mediators attract other leukocytes into tissue

how is intradermal skin testing used in cases of atopic dermatitis?

• NOT used to diagnose (normal dogs & cats can test positive)

• used to figure out which antigens patient is sensitive to and formulate immunotherapy

treatment of atopic dermatitis

• if possible, minimize exposure to allergen

• treat any secondary infections (ex. pyoderma or otitis externa)

• immunotherapy with “allergy shots” or “allergy drops”

  • designed to ↑ T_regs , ↓ T_H2 & shift antibody production from IgE to IgG

  • can take several months to a year to see effect

• glucocorticoids during crises

• treatments to reduce/suppress pruritus

  • apoquel

  • cytopoint

feline asthma pathology

• T_H2 response & IgE production → mast cells

• eosinophils are recruited to the airways during later stages by inflammatory mediators released by a variety of cells (lymphocytes, activated epithelium)

  • → eosinophilia

treatment of feline asthma

• medications → multiple routes, including orally & by aerosol

  • glucocorticoids (anti-inflammatory)

  • bronchodilators

• environmental modulation: reduce exposure to allergens (dust, molds, pollens) & irritants (e.g. candles, air fresheners)

examples of type II hypersensitivities

• immune-mediated hemolytic anemia

• myasthenia gravis

• pemphigus foliaceus

what signalment is most affected by immune-mediated hemolytic anemia? what is the prognosis?

• one of the most common immune-mediated diseases in dogs

  • usually affects middle-aged female dogs

• long-term prognosis is guarded

  • high mortality rate in dogs (~50%); mortality rate lower in cats

what are causes of immune-mediated hemolytic anemia?

• primary (idiopathic) → more common in dogs

• secondary → manifestation of underlying disease process

  • infectious (rickettsial organisms, heartworm, M. haemofelis)

  • neoplastic (leukemia, lymphoma)

  • drugs (cephalosporin & penicillin)

what is the typical appearance of mucous membranes in IgM-mediated IMHA? why?

• pale MM

• IgM (large pentamer) → ↑ agglutination → ↑ complement activation & membrane attack complex → intravascular RBC lysis

what is the typical appearance of mucous membranes in IgG-mediated IMHA and why? what are other clinical manifestations?

• icteric MM

• IgG → ↓ agglutination → phagocytosis by splenic macrophages → splenomegaly & hepatomegaly

  • high RBC breakdown → increased bilirubin

diagnostic findings consistent with IMHA

• severe anemia

  • may be regenerative

  • spherocytes (dogs only, IgG-mediated)

  • ghost cells (IgM-mediated)

• persistent autoagglutination of RBCs

• positive coombs’ test (direct antiglobulin test)

• bone marrow biopsy shows phagocytosis of erythroid precursors (if non-regenerative)

slide agglutination test

• dilution of blood with saline will eliminate rouleaux

• true agglutination will persist because antibodies to RBCs are response for clumping

direct antiglobulin test (coombs’ test)

• washed RBCs from patient with IMHA → add species specific anti-IgG or IgM → agglutination

• indicated when persistent autoagglutination is NOT present & suspect IMHA

bone marrow aspirate (non-regenerative IMHA)

• immune response targets erythroid precursors → phagocytosis of erythroid precursors

  • immature RBCs destroyed as they are produced

• erythroid hyperplasia

primary IMHA treatment

• glucocorticoids

  • inhibits Fc-receptor-mediated phagocytosis of RBCs by macrophages

  • inhibits complement activation

  • decreases production of pro-inflammatory cytokines

• initial doses high to induce remission, then taper down to maintenance level

what are second-line IMHA treatments? when should they be used?

• immunosuppressive agents

  • azathioprine → dogs

  • chlorambucil → cats

• added if:

  • severe disease

    • intravascular hemolysis or transfusion dependency

    • lack of response to glucocorticoid therapy alone

  • concurrent thrombocytopenia

  • significant glucocorticoid side effects

acquired myasthenia gravis pathology

• antibodies directed against acetylcholine receptors on muscle cells → receptor degradation or blockage of neuromuscular transmission

• causes muscle weakness; megaesophagus

what signalment is affected by myasthenia gravis?

• bimodal distribution in dogs

  • 2-4 years & 9-13 years

• rare in cats

signs of muscle weakness (myasthenia gravis)

• focal with selective involvement of esophageal, pharyngeal, and facial muscles

• diffuse with signs of generalized muscle weakness

• acute fulminating — rapid onset of appendicular muscle weakness, megaesophagus, & collapse

myasthenia gravis diagnosis

• detection of antibodies to acetylcholine receptor (gold standard)

• physical exam & radiographs (megaesophagus ± chest mass [thymoma])

• tensilon response test

  • inhibits acetylcholinesterase → acetylcholine can remain longer in the synaptic cleft & stimulate any remaining receptors

  • currently not being manufactured

• electromyogram

  • decreasing amplitude

myasthenia gravis treatment

• first line — acetylcholinesterase inhibitors

• immune suppression — controversial

  • (megaesophagus — risk of aspiration pneumonia)

  • use only if necessary

• plasmapheresis

  • helpful in severe disease or refractory cases

what signalments/species does pemphigus foliaceus affect?

• dogs, cats, horses

• most common immune-mediated skin disease

• middle-aged to older animals; some breed dispositions

pemphigus foliaceus clinical signs/distribution of lesions

• superficial pustules (subcorneal, vesicopustules) — fragile!

• lesions break open → crusting, exfoliation, erythema, erosions

• lesions often GENERALIZED

• face - bridge of nose & muzzle

• ears

• groin

• footpads

pemphigus foliaceus pathology

• autoantibodies directed against desmosomes (extracellular cement protein of epidermis; anchors epidermal cells)

• neutrophils respond to autoantibody stimulus but no bacteria

• rounding up of keratinocytes (acantholytic change) & presence of non-degenerative neutrophils

pemphigus foliaceus treatment

• glucocorticoids most commonly used & are the first choice

  • combination treatment — azathioprine (dogs) or chlorambucil

• treat any secondary bacterial infections that may be present

• avoid medications that may predispose to immune attacks

  • drugs that contain carbon-bonded sulfhydryl (-SH) group — beta-lactam antibiotics & trimethoprim-sulfa drugs

• avoid sunlight — UV radiation exacerbates the disease