32. immune mediated disease part 2 (type III & IV hypersensitivities)

mechanism of type III hypersensitivity

• formation of small, soluble immune complexes that are not cleared by phagocytes → antigen-antibody complexes deposit in tissue

  • → local activation of complement (attract neutrophils)

  • → inflammation & tissue damage

what are the two examples of type III hypersensitivities discussed in lecture?

• target → blood vessels → purpura hemorrhagica

• target → joint synovium → immune-mediated polyarthritis (IMPA)

what is the major infectious agent associated with purpura hemorrhagica in horses? what is the underlying pathology?

• streptococcus equi equi

• large amount of antigenic material (antigen excess; ex. draining abscesses)

• with strangles, usually involves binding of both IgA & IgG complexes to M-like protein from Strep. equi

purpura hemorrhagica clinical signs

• marked edema of head, ventral abdomen, and limbs

• petechial hemorrhages of mucous membranes

• may have signs of colic with GI infarction

diagnosing purpura hemorrhagica

• history of infection, vaccination, or drug administration (although, may be idiopathic)

• clinical signs

• rule out other causes of vasculitis:

  • anaplasma

  • ehrlichia equi

  • babesiosis

  • equine viral arteritis

  • equine herpesvirus

  • immune-mediated thrombocytopenia

purpura hemorrhagica treatment

• address underlying cause & remove it

  • antibiotics if bacterial infection suspected/present

  • stop using drugs if suspect trigger

• suppress immune system → glucocorticoids (dexmethasone & prednisolone)

• supportive care: hydrotherapy, leg wraps, nasogastric tube if dysphagic

pathophysiology of immune-mediated polyarthritis (IMPA)

antigen-antibody complexes become trapped in synovium

• → activates complement

• → complement attracts & activates neutrophils

• → tissue damage, edema, and joint swelling

most commonly noted in smaller joints (carpus or tarsus)

what is the typical cytologic finding in synovial fluid of a patient with IMPA?

increased number of neutrophils without evidence of infection

categories of non-erosive IMPA

• idiopathic: most common in dogs

• reactive: 25% of cases have underlying infection (viral, bacterial, fungal)

  • can be caused by vaccine or drug

• enteropathic (rare): leaky gut → exposure of antigens to immune system

• neoplasia-associated (rare)

what are examples/causes of reactive IMPA?

• example: lyme arthritis

• history of current or previous use of inciting drugs

  • ex. sulfonamide treatment in Doberman dogs

• vaccine-induced usually occurs within 30 days of vaccination

• signs usually resolve within 2-7 days of:

  • antimicrobial treatment

  • discontinuing the drug (if inciting cause)

  • spontaneously (vaccine-induced)

pathology of drug-induced IMPA

hapten molecule (drug) + carrier molecule → conjugate induces immune response → antibodies against conjugate produced

IMPA treatment

• treat underlying factors if present (infection)

• immune-suppressive doses of corticosteroids

  • refractive cases may need additional immune suppression (azathioprine)

mechanism of type IV hypersensitivity

antigen presented to antigen-specific T cells (usually T_H1) → T cells become activated & produce cytokines → trigger leukocyte activation & infiltration (lymphocytes, macrophages) of target tissue → inflammation & tissue injury

organ-specific autoimmune disease caused by T cells are characterized by what?

chronic, progressive inflammation / tissue injury and fibrosis

what are the two examples of type IV hypersensitivities discussed in lecture?

• hypothyroidism (lymphocytic thyroiditis)

• keratoconjunctivitis sicca

canine hypothyroidism clinical signs

associated with inadequate thyroid function:

• lethargy/inactivity

• generalized weakness

• unexplained weight gain

• mental dullness

• alopecia/excessive hair shedding

• secondary skin infections (parasitic, bacterial, fungal)

histologic findings of lymphocytic thyroiditis

thyroid tissue infiltrated with lymphocytes & macrophages → destruction of thyroid gland by cell-mediated immune processes

canine hypothyroidism diagnostic findings

↑ thyroid stimulating hormone (TSH) with ↓ free thyroxine (fT4)

canine hypothyroidism treatment

• lifelong supplementation with thyroid hormone → levothyroxine

• correct any secondary problems (skin infections)

• immune suppression NOT used to treat (damage to thyroid already done)

keratoconjunctivitis sicca (KCS) pathology/cause

• most common cause is cell-mediated destruction of lacrimal gland with secondary tissue atrophy

  • → decreased production of aqueous portion of tear film → dry eye

what is the most consistent clinical sign of KCS?

mucoid to mucopurulent ocular discharge

what dog breeds are at risk for immune-mediated KCS?

• american cocker spaniel

• cavalier king charles

• english bulldog

• lhasa apso

• west highland white terrier

KCS diagnosis

• schirmer tear test <10 mm/min

  • (normal > 15 mm/min)

• history

• clinical signs

keratoconjunctivitis sicca treatment

• lifelong treatment

• stimulate natural tear production

  • topical cyclosporine A → blocks IL-2 production & inhibits T-helper + CTL function in the lacrimal gland

  • topical tacrolimus (similar mechanism as cyclosporine, more potent)

• provide tear replacements → artificial tears

• control secondary infections → topical antibiotics

• reduce inflammation → topical corticosteroids (ensure absence of corneal ulcers)