D’YOUVILLE COLLEGE
PMD 604 - ANATOMY, PHYSIOLOGY, PATHOLOGY II
Lecture 6: Hypersensitivities, graft rejection, immunodeficiencies
G & H chapters 34, 35 & R chapter 5
1.
Hypersensitivities:
- hypersensitivity refers to circumstances in which immune system
inappropriately attacks harmless antigens, or immunological self-tolerance fails
(autoimmunity), or immunological response is excessively vigorous; result is damage to
healthy tissues
- four types are identified (may overlap) (table 5 – 1)
• immediate hypersensitivities (type I): also known as allergies
- immediate hypersensitivity responses may be localized (atopic =
genetically based) or systemic (anaphylactic = ‘without guarding’)
- mast cells (also basophils) are main vehicles for this hypersensitivity
- relatively innocuous antigens (allergens) provoke sensitization, which
entails proliferation of IgE type antibodies (reagins) that bind to receptors on mast
cells (fig. 5 – 8 & ppt. 1)
- subsequent antigen encounters involve Ab cross linking & instigate a
disproportionately strong response involving mast cell degranulation that releases
histamine and other mediators of inflammation (e.g., eosinophil chemotaxins,
leukotrienes [= slow reacting substance of anaphylaxis] & prostaglandins, etc.) (fig. 5 – 9 &
ppt. 2)
- elevated eosinophil levels constitute part of late phase (5 – 10 & ppt. 3)
- disease states include urticaria (hives), rhinitis (hay fever), eczema,
conjunctivitis, & allergic asthma
treat with antihistamines or epinephrine; steroids & NSAIDS block late
phase responses, which take longer to develop (several hours compared to minutes
for immediate response)
• antibody-mediated hypersensitivities (type II)
- NK cells & phagocytic cells are activated by antibodies (often against
‘self’ antigens = autoimmunity) or antibodies against red blood cell antigens
(transfusion reaction) (antibody-dependent cellular cytotoxicity – ADCC)
- IgG class antibodies (complement fixing) are the instigators via
opsonization, complement fixation & cellular dysfunction mechanisms (fig. 5 - 11 & ppt. 4)
- diseases (table 5 – 3):
- myasthenia gravis (cytotoxic attack of muscle motor end plates);
severe muscular weakness &/or paralysis results
PMD 604, lec 6
- p. 2 -
- Goodpasture’s syndrome (attack on glomerular or lung tissues);
nephritis or restrictive pulmonary disease (hemorrhage and fibrosis of lung tissue)
- Graves disease (thyrotoxicosis) results from attack of TSH receptor
- transfusion reactions
PMD 604, lec 6
- p. 3 -
• immune complex hypersensitivities (type III)
- imbalance between antigen level and antibody level produces departure
from normal immune response: circulating antigen-antibody complexes (immune
complexes) settle on vascular walls instigating vessel damage, formation of small
clots & inflammation (fig. 5 – 12 & ppt. 5)
- immune complex deposits can afflict various tissues: nerve (neuropathies),
kidney (glomerulonephritis), skin (rashes), joints (rheumatoid arthritis), & heart (valve
damage)
- systemic lupus erythematosus (SLE), an example of immune complex
diseases (see table 5 – 4), may victimize one or more of the above tissues
- autoimmune condition (genetic origin) (fig. 5 – 19 & ppt. 6)
- autoantibodies attack nuclear self-antigens (fig. 5 – 20 & ppt. 7)
• cell-mediated (delayed) hypersensitivities (type IV)
- delivered by CMI: T lymphocytes & macrophages instigate inflammation
or direct cell killing (fig. 5 – 13 & ppt. 8); inflammatory lesion is a granuloma (fig. 5 –
15 & ppt. 9)
- viral infections may elicit type II response (NK cells) or type IV (CTL cells)
- contact dermatitis (allergens from poison ivy, poison oak)
- anaphylactic reactions may result with type IV as well as type I: allergens
such as insect venoms, plant resins (see above), drugs (e.g., penicillin), certain foods (e.g.,
glutens – celiac disease); systemic anaphylaxis may cause widespread tissue damage
and/or shock (anaphylactic shock)
• tissue transplants – grafts bear MHC (HLA) antigens on cell surface that are
immunogenic (excepting autografts - one's own tissue or isografts - monozygotic twin's
tissue); immunogenic (foreign) tissues may from another person (allografts) or from a
different species (xenografts), e.g., from pig or sheep, etc.
- allografts introduce MHC (HLA) incompatibility that elicits cell-mediated
rejection of foreign tissue (type IV hypersensitivity response); APCs in the graft or
APCs of host may mediate immune responses (fig. 5 – 16 & ppt. 10)
- AMI rejection (via complement fixation) may occur in previously sensitized
recipients
- improving graft survival – tissue-typing for best match
- purge donor tissue of APC
- purge host’s TH cells to weaken immune response
- post transplant immunosuppression therapy & administration of
antibiotics to minimize vulnerability to opportunistic infections
• graft vs. host reaction: transplanted lymphoid tissue, e.g., bone marrow
may mount immunological attack upon host tissues
PMD 604, lec 6
2.
- p. 4 -
Immunodeficiencies:
• primary: genetic deficiencies of T cells or B cells or both (= severe combined
immunodeficiency disease [SCID] (fig. 5 – 29 & ppt. 11)
•acquired:
• HIV/AIDS (human immunodeficiency virus infection followed by acquired
immunodeficiency syndrome)
- enveloped virus with RNA genome + reverse transcriptase = retrovirus
(fig. 5 – 30 & ppt. 12)
- many subtypes of HIV render it elusive to immunization measures
- infects target cells via CD4 receptors and certain coreceptors (fig. 5 – 31 &
ppt. 13)
- first infects macrophages/monocytes and then T4 lymphocytes; enters
target cell by endocytosis and produces a DNA genome (from RNA template); DNA
genome inserts into host DNA (provirus)
- ‘cycling’ of host cell (stimulated by an interleukin) triggers virus
reproduction (involves proteases that cleave HIV polyproteins) and infection of other
target cells (fig. 5 – 32 & ppt. 14)
- disease progresses from flu-like symptoms (acute phase) to
seroconversion (appearance of HIV antigens in blood); infection may be held at bay
for variable length of time (chronic phase) by CTL cells until T4 cell numbers decline
to a point of paralyzing the CTL response; disease then progresses to ARC (AIDS
related complex) then to AIDS (crisis phase) (fig. 5 - 34 & ppt. 15)
- progressive decline of T4 cell population (fig. 5 - 33 & ppt. 16)leads to
widespread breakdown of immune responses: neuropathies in brain tissue, neoplasms,
e.g., Kaposi sarcoma, (due to deficient tumor surveillance), opportunistic infections
(PCP – Pneumocystis pneumonia)
- transmission via exposure to body fluids containing infected T cells (less
likely free virus) – promiscuous sexual activity, IV drug use with shared needles,
transfusion with contaminated blood, accidental needle stick or other exposure to
fluids of infected patient
- maternal-fetal transmission: transplacental, at parturition or during
nursing
- reverse transcriptase inhibitors and other drugs that block reverse
transcription + protease inhibitors are among contents of ‘cocktails’ administered to
HIV infected patients; while not a cure, they appear effective in delaying progression
to AIDS