Immunology 6 - Hypersensitivity (ii)

type 2

Ig-mediated

binds to tissues + activates complement

inflamm cell influx + tissue damage

e.g. in autoimmunity

anti-glomerular basement membrane disease

green immunofluorescence on membrane = IgG inflamm rim

penicillin allergy

Igs made in response to penicillin coated RBCs

activates complement

MAC - haemolysis

C3b - opsonisation + phagocytosis

"special' type 2 hypersensitivity

Igs bind to functionally important Rs as agonists or antagonists

antagonising = MG

ACh R

muscle fatiguability

agonising = Grave's

TSH R

hyperthyroidism + non-thyroid effects (e.g. exophthalmos)

Dx

lab test = tissue-specific Igs

100% sensitive (esp in acute untreated disease)

Bx (look for Ig deposition)

Pemphigus + Pemphigoid

rare autoimmunity affecting skin + mucous membranes

lab test less sensitive

type 3

Ig binds to antigen either in blood or tissue

activates complement (release of inflamm mediators, C3a,4a,5a which induces mast cell degranulation)

rheumatoid vasulitis

SLE

immune complexes are normal

supposed to be removed by the reticuloendothelial system (phagocytes in liver + spleen)

abnormal when there's too many

instead deposited in tissue + blood vessels (! occlusion)

lab tests

complement studies (look for low C3+4 due to increased consumption)

complement degradation product studies (not routinely available)

CH100 (rule out complement deficiency)

look @ connective tissues (ANF, rheumatoid factor, cryoglobulins-abnormal Igs, anti-dsDNA, anti-extractable nuclear antigen/ENA)

banding: clotting green immunofluorescence

type 4

delayed

APC to Th1 cells - activation

CKs (e.g. IFNgamma, TNFalpha, IL12) act on vasc endothelium + activate macrophages - granuloma lesions form

RA

cellular rejection

antineutrophil cytoplasmic antibodies (ANCAs)

increase neutrophil's ability to damage endothelium via activating resp burst

aid neutrophil adhesion to endothelium (common in vasculitis)

anti-phospholipid syndrome

anti-cardiolipin antibodies contribute to thrombosis

autoimmune hypercoaguable state

mechanism poorly understood

passive transfer induces disease (animal studies)

e.g. Langerhan's in skin

Therapeutic Igs

polyclonal

monoclonal

problem: admin of a foreign product

ATG from rabbits/horses

anti-D (human, for rhesus incompatibility)

OKT3

not used as much

anti T cell

once off use only or else SEs next time due to self Igs against this Ig

can be humanised

infliximab (anti-TNF)

Natalizumab/Tysabri

how is this done?

  1. fuse mouse B cells with antigen + myeloma cells (malignant immortal plasma cells)
  1. grow on medium selective to hybrid cells
  1. grow on antigen-specific medium
  1. clone

labour intensive

can be chimeric

10% animal (in variable region)

90% human (in constant region)

even less animal (only in 3 hypervariable regions)

not much therapeutic benefit compared to chimeric

10% make Igs against Ig (reaction)