Hypersensitivity recap, chronic intestinal inflammation + granuloma formation

what is type 1 hypersensitivty?

• IgE mediated - immediate

what is type 2 hypersensitivity?

• cytotoxic IgG/IgM - involves antibodies and antigens → ADCC and complement

what is type 3 hypersensitivity?

• IgG/IgM mediated

  • antigen-antibody complexes → found in tissues

what is type 4 hypersensitivity?

• delayed T-cell mediated

  • CD4+ Th1/CD8+ cells + macrophages

key components of type 1 hypersensitivity

• Th2 cells

• IgE antibodies

• mast cells

• eosinophils

what is the sensitisation sequence of type 1 hypersensitivity?

1. exposure to antigen

2. APC present antigen → naive CD4+ T cell

3. IL-4 → B cell class → IgE production

4. IgE binds to mast cell → senstisation complete

what happens upon re-exposure with type 1 hypersensitivity?

• IgE on mast cells

• crosslink allergen

• mast cell degranulates

• histamine/prostaglanding released

VASODILATION AND OEDEMA

what occurs with type 1 hypersensitivty in the late phase?

• eosinophil increase, sustained inflammation

What are the key componetns of type 2?

• IgG/IgM antibodies

• complement

• phagocytes/NK cells

what is the sensitisation stage of type 2?

• exposure to antigen on cell surface

• intrinsic/extrinsic antigen

• IgG/IgM produced against cell surface antigen

what happens upon re-exposure of allergen with type 2?

• complement: lysis + opsonisation = phagocytosis

• ADCC = NK cells destroy antibody coated cells

• intrinsic receptor disruption = blocks/stimulates receptors

for type 2 antibody mediated cytotoxicity, state what the option is for intrinsic vs extrinsic

1. antigen source

2. typical cause

3. immune recognition

4. clinical relevance example

Intrinsic	extrinsic
Host’s own cells	External agents modifying cells
autoimmune reaction	drugs, infections, transfusions
self mistaken as foreign	self modified to appear foreign
Myasthenia gravis, IMHA	penicillin reaction, transfusion mismatch

Type 3 key components are?

1. IgG/IgM antibodies

2. soluble antigens, not cell bound

3. immune complexes

4. complement system/neutrophils

how we distinguish type 2 from type 3?

• type 2 = antigen on cell surface

• 3 = antigen is soluble/circulating

what is the process of sensitisation with type 3?

• initial exposure → IgG/IgM antibody production

outline complex formation of type 3

1. circulating IgG binds soluble antigen

2. either large (antibody excess) or small complexes (antigen excess) form

3. small complexes cause problems

why do small complexes with type 3 cause problems?

• this is where we have antigen excess therefore difficult to clear

• they deposit in tissues → tissue damage

with type 3, are small or large complexes easier to clear?

• large - due to antibody excess

what are the preferential sites for type 3 small complex deposition?

• kidney

• joints

• blood vessel walls

• skin

what is the tissue damage mechanism for type 3

• complement activation (C3a + C5a)

• neutrophil recruitement to location

• neutrophils release lysosomal enzymes = tissue damage

• inflammation/vasculitis

key cells involved in type 4?

• T-lymphocytes

• macrophages

• dendritic cells

characteristic cytokines of type 4?

• interleukin 12

• INF-gamma

• TNF-alpha

• interleukin-2

what isn’t involved in a type 4 reactions?

• antibodies

function of IL-12?

• drives Th1 response of CD4+ naive T cells

• initiates cell-mediated response

function of INF-gamma?

• activate macrophages in Gi mucosa

• increase defence against intracellular pathogens

function of TNF-alpha?

• increase permeability of GIT via tight junction disruption

  • role in granuloma organisation/maintenance

function of IL-2?

• enhances clonal expansion of antigen specific T cells

• activates Cytotoxic T cells to eliminate infected cells

• essential for development of T regulatory cells

sensitisation phase of type 4

1. APC presents antigen via MHC II

2. naive CD4+ t cells → TH1 cells

• IL-2 → clonal expansion → memory T cells

phase 2 of type 4?

• effector response - Th1 memory cells release IFN-gamma + TNF alpha

  • macrophages recruited and activated

  • CD8+ cytotoxic T cells activated

what is phase 3 of type 4?

• Th1 → Th2 switch

  • Th2 drives antibody production (but this is ineffective)

  • immune suppression reduces T cell function

• granuloma formation → failed pathogen clearance

  • macrophages → muclinucleated giant cells

what is a type 1 hypersensitivity reaction?

• food allergy GI link

  • IgE mediated response to dietary proteins

• atopic dermatitis

what symptoms with a type 1 food allergy GI disease are show in cats vs dogs?

dogs - dermatological + GI signs

cats - Gi signs more prominent

how do we treat type 1 food allergy?

• dietary exclusion trial

atopic dermatitis:

1. what type of sensitivity reaction?

2. why do we get pruritus

3. how do we diagnose + treat?

1. type 1

2. IL-31

3. clincal signs + exclusion of other pruritic disease, serological testing. Treat with lokivtemab

3 types of type 2 clinicla reactions

1. myasthenia gravis

2. immune mediated haemolytic anemia

3. drug reactions

what is myasthenia gravis?

• intrinsic autoimmune disease

• see impaired skeletal muscle neuromuscular transmission, weakness, exercise intolerance

  • megaoesophagus is seen

how dow e diagnose myasthenia gravis?

• AChR radioimmunoassay + clinical signs

how do we treat myasthenia graivs?

• symptomatic/supportive

what is immune mediated haemolytic anemia?

• intrinsic autoimmune disease where the erthryoctes are targetted

• causes complement-mediated lysis of erythrocytes

how do we diagnose then treat IMHA?

• coombs test + blood smear

• immunosuppressives, support and transfusion

what are 2 type 3 condiitons?

• glomerulonephritis

• purpura haemorrhagica in horses

what is glomerulonephritis

• immune complexes get trapped in glomeruli

• complement activation → inflammation

what is purpura haemorrhagica in horses?

• often follows strangles

• where we get immune complex deposit in vessel walls → vasculitis, petechial/purpuric skin lesions

what are 2 example type 4 conditions?

1. granulomatous enteritis

2. Johne’s disease

what is granulomatous enteritis?

• chronic intestinal inflammation - ileum is most affected

• disrupts mucosal integrity and barrier function

what are 5 key signs of inflammation?

1. redness - rubour

2. heat - calor

3. swelling - tumour

4. pain - dolor

5. lack of function

how long does acute vs chronic inflammation last?

• acute lasts several days, at most weeks

• chronic lasts for weeks, months or years

chronic inflammation:

1. when does it occur

2. what usually causes it?

3. what may form as a result?

4. what is a granuloma an example of?

1. no return to steady state conditions after acute inflammation

2. infectious causes may be immune mediated

3. granuloma

4. delayed type 4 hypersensitivity response

6 causes and disorders of chronic inflammation

1. autoimmune disorders

2. exposure to toxins

3. chronic exposure to irritant/foreign material

4. auto-inflammatory syndromes

5. infection

6. trauma

what are 4 disorders associated with chronic inflammation?

1. osteoarthritis

2. gingivitis

3. hyper-inflammatory syndrome in weimaraner

4. diabetes

what are 4 conditions of chronic inflammation with granuloma formation

1. canine lick granuloma

2. persistent bacterial infection: brucellosis, tuberculosis, Johne’s disease

3. coccidiosis

4. suture granuloma

what cells are involved in granuloma formation?

• macrophages

• T cells

Outline macrophage and T cell involvement in granuloma formation

1. activated macrophages constantly secrete TNF-alpha + other proinflammatory cytokines - promote influx of T-cells + others.

2. T cells around periphery secrete INF-gamma - contributes to chronic reactivity of macrophages

3. the macrophages may develop into epithelioid cells

4. if prolonged → epithelioid cells fuse together forming giant/Langhans cells

why may we get organ damage with granulomas?

• T cell and macrophage stimulating fibroblasts → fibrosis

to cause granuloma breakdown, what cytokine needs to be removed?

• TNF-alpha

pros of granuloma formation?

• focal killing point in which micro-organisms may eventually be killed

• they prevent dissemination since it ‘walls off’ micro-organisms

what are cons of granuloma formation?

• break-down → bacteria dissemmination

• may have severe tissue necrosis, hence organ dysfunction

• fibrosis and tissue thickening with organ function impairment due to granuloma

How may a patient with a suture granuloma present?

• spayed dog

• anorexia + apathy last week

• fever, dehydration, enlarged lymph nodes + tense abdomen

• rediography will show a mass located at the left ovary

chornic entercolitis:

1. most evident symptom?

2. 4 causes?

3. how many forms?

4. in what animal is it the most common GI disorder?

1. chronic diarrhoea

2. idiopathic, chronic infection, allergic response, genetic component

3. 4 forms

4. old cats

what 4 forms of chronic enterocolitis are there?

1. lymphocytic plasmocytic enteritis

2. eosinophilic enteritis

3. neutrophilic colitis

4. granulomatous colitis

lymphocytic plasmocytic enteritis:

1. most common form of IBD in what

2. characterised by what

3. difficult to differentiate from what in cats?

4. what will we see histologically?

1. dogs and cats

2. increased lymphocyte + plasma cell infiltrate in lamina propria - most commonly in ileum + colon

3. small cell lymphoma

4. dark tissue due to vast number of lymphocytes

eosinophilic gastroenteritis:

1. what cell type is the infiltrate?

2. due to what?

1. eosinophils

2. normall chronic parasitic infections/allergy

eosinophilic (gastro)enteritis:

1. known as what in cats

2. variant of what

3. due to what

4. where do the cells go

5. 6 most commonly affected organs

6. prognosis?

1. hypereosinophilic syndrome

2. eosinophilic enteritis

3. overproduction of eosinophils in bone marrow

4. into multiple organs

5. bone marrow, small intestine, liver, spleen, mesenteric + peripheral lymph nodes, skin lesions

6. poor

neutrophilic colitis:

1. cell type

2. 5 possible causes?

1. neutrophil infiltrate

2. idiopathic, normal bacterial microbiota response, campylobacter invasion, trichomonas foetus infection, mucosal erosions inducing neutrophilic infiltrates due to loss of mucosal barrier integrity

granulomatous colitis:

1. common?

2. causes what?

3. what do we see histologically?

4. true granulomas?

5. what may be the cause?

6. what was lasting remission seen with

1. no, rare

2. thickened, partly obstructed bowl segment - ileum most commonly

3. foamy, large, PAS +ve macrophages in colonic mucosa

4. no

5. E.coli causing macropahges to respond certainly

6. eradicating E.coli

Chronic gastroenteritis: how do we manage it?

1. treat any infectious causes

2. change diet next

3. may use antibiotics/anti-inflammatories

4. should try therapeutic deworming - due to ova shedding by whipworms - do even if faecal tests are negative

what is the short term vs long term prognosis of chronic colitis?

• good short term

• poor long term when looking for complete resolution without relapses

A boxer dog presents with frequent small volume diarrhoea, haematochezia (bright red blood in stool), mucoid faeces, tenesmus, lethargic and cachexia (muscle loss, weight loss, lethargy).

1. what is your differential diagnosis?

2. what is it likely to be/reveals what it is

3. treatment plan?

1. idiopathic IBD, enteric parasites, infectious agents

2. ganulomatous colitis

3. enroflaxin