5.1, 5.2, 5.3 – Hypersensitivity, Organ rejection/autoimmune, immune deficiency

Type I – IgE-mediated hypersensitivity. Immediate, within minutes
What happens:
1. Sensitisation – Exposure to antigen bridges Fc receptors for IgE. This triggers mast cells to release mediators
2. Release of preformed mediators
-Histamines – Vasodilation, vascular permeability, smooth muscle contraction, mucus secretion
-Chemokines – Attract neutrophils & eosinophils
-Proteases – Tissue damage, kinin generation, activation of complements
Release of newly formed mediators
-Prostaglandins – Intense bronchospasm & mucus secretion
-Leucotrienes – 1000x more active than histamine
3. Additionally for asthma/eczema
-Activation of sensitised T-cells (Th2 subset)
-IL-4, IL-5, IL-13 release

Types of Type I
1. Atopic – Inherited overproduction of IgE antibodies against common environmental allergen
-Allergic rhinitis, asthma, eczema
2. Anaphylaxis – Generalised mast cell & basophil degranulation
-Peanuts, Latex, penicillin
3. Anaphylactoid – Similar to anaphylaxis but not IgE mediated
-Radiographic contrast media, anaesthetics

Type II – IgG, IgM mediated. Antibodies react to cell-bound antigens = phagocytosis/lysis of target cell
Types & Examples
1. Antibodies formed against drugs/metabolites results in cell destruction (bystander lysis)
-Haemolytic anaemia (Antibodies formed against RBCs)
-Thrombocytopaenic purpura (Antibodies formed against platelets)
2. Antibodies formed against normal cell functioning sites e.g. hormone receptors
-Graves disease (antibodies formed against TSH)
-Pemphigus vulgaris (antibodies formed against intercellular adhesion cells)
-Type II diabetes (antibodies formed against insulin receptors)

Type III – Deposition/formation of immune complexes which results in
-Complement activation
-Platelet aggregation
-Neutrophil attraction
-Local inflammation
Occurs in:
1. Persistent antigen exposure
2. Abnormal host immune reponse
3. Local defects
Examples
1. Post-streptococcal glomerulonephritis
-10-12 days after strep throat
-IgG & C3 immune complex deposition in glomerular basement membrane
2. Systematic Lupus erythematosus (SLE)
-Own nuclear antigens attacked
-Results in nephritis, skin lesions, arthritis (butterfly rash)

Type IV – Delayed hypersensitivity, mediated by T-lymphocytes. 2-3 days
What happens:
1. Sensitisation
-T-lymphocytes react with antigen
-Release IL-2,, interferon-alpha, TH1-cytokines
2. Delayed reaction (2-3 days)
-Local inflammation with T-lymphocytes, macrophages, eosinophils
Examples :
1. Contact dermatitis – small, reactive molecules that aren’t immunogenic by themselves
Pathogenesis – Induction phase – Langerhans cells binds the hapten-carrier protein complex & presents it to T-lymphocytes
-Elicitation phase – Effector T-cells migrate to skin & release cytokines & induce skin inflammation
-Patch testing – Reaction site inspected after 2-4 days for inflammation & induraiton
2. Tuberculin reaction e.g. Mantoux test
-Purified protein derivative of mycobacterium tuberculosis
-Not immune = no reaction
-Immune = Inflammation & induration after 2-3 days
3. Normal immune response to mycobacterium tuberculosis & leprae (is delayed hypersensitivity)
-If no hypersensitivity response, person develops tuberculosis or leprosy

5.2 Autoimmunity
1. Autoimmune vs autoimmune disease
Autoimmune – An immune response against self-antigens
Autoimmune disease – Tissue damge or disturbed physiological function from an autoimmune response
2. Criteria that autoimmune response causes disease
1. Demonstrate reactivity to self-antigen
2. Isolate this self antigen
3. Induce reactivity by immunisation in animal
4. Show similar pathological change as humans in this immunised animal
3. Organ specific vs non-organ specific
Organ specific – Autoantibody may target cell surface or intracellular molecule
Non-organ specific – Slef-antigen widely distributed in the body
4. Epidemiology of autoimmune disease
-3% of poopulation, more common in women, peak onset 15-65 y/o
-MS, rheumatoid arthritis, Type I diabetes
5. Aetiology of autoimmune disease
1. Genetic – Some single gene-defects in apoptosis, usually multiple genes. Strongest association w/ alleles of MHC
2. Environmental – 1. Hormones (females – oestrogens peak onset), 2. Infection (molecular mimicry), 3. Drugs (structural similarity to self), 4. UV radiation (can modify self-antigens)
6. Tissue damage mechanisms in autoimmune disease
Mediated by
-Autobody or immune complexes
-CD4+ T-cell mediated activation of macrophages or cytotoxic -T cells
– Combination
7. Sjogren syndrome – CD4+ T-cell reaction against unknown antigen in ductal epithelial cells of exocrine cells
8. Treatment of autoimmune disease – Replacement of organ function / Suppression of autoimmune response

Organ Transplant
1. Definitions
-Haloptype – A group of genes in an individual inherited from a single parent
-Allel – Alternative form of a gene
-Allogenic grafting – Between genetically different people
-Autologous grafting – From one part of a person’s body to another
-Xenogenic grafting – Between species
2. MHC
-Human antigens are called HLA (Human Leucocyte antigens)
-In humans they are encoded by a segment of chromosome 6 called MHC
-HLA system is extremely polymorphic (multiple alleles at each locus)
-MHC 1 – most nucleated cells
-MHC 2 – Expression normally restricted to antigen-presenting cells
-MHC 3 – Constitute early complement proteins C2 & C4
3. Pathogenesis of graft rejection
1. Afferent phase – MHC molecules on dendritic cells of donor are recognised by recipient CD4+ T cells
2. Effector phase – CD4+ T-cells enter graft & recruit effector cells, responsible for tissue damage (Macrophages, NK cells, B-lymphocytes, CD8+ T-cells)
-Most important cytokines in graft rejection are IL-2, interferon-alpha
-Critical parts that need to be attacked for rejection to occur are endothelium & parenchymal cells of the organ
4. Kidney graft rejection types
1. Hyperacute rejection
-Minutes-hours, must be removed
-Circulating cytotoxic antibody reacts with MHC class I antigens in donor kidney
-Acivation of complement = influx in polymorphonuclear leucocytes, platelet aggregation, obstruction of vessels = ischaemia = infarction = decreased renal function = anuria
2. Acute rejection
-Few days-weeks, immunosuppressive therapy reverses kidney damage
-Acute rejection associated with increased expression of MHC class I & II antigens in graft & early infiltration of CD8+ T cells
-Results in mononuclear infiltrate in renal cortex & necrosis in arterial walls
3. Chronic rejection
-Months-years, slow progressive renal failure & hypertension
-Does not respond to imunosuppressive therapy
-Histologically 1. Thickening of glomerular basement membrane
2. Hyalinisation of glomeruli
3. Interstitial fibrosis
4. Proliferation of endothelial cells
5. Complications of immunosuppresion
1. Increased susceptibility to infections (viral & fungal)
2. Recurrence of original disease
3. Increased incidence of malignancies (e.g. lymphoma of kaposi sarcoma)
6. Graft vs host & oral complications
1.haemopoietic stem cell transplant from bone marrow only chance to treat:
Aplastic anaemia, leukemia, immunodeficiency disorders, inborn errors of metabolism
1. Complications of HSCT are failure of graft, infection, GVHD
2. GvHD occurs in allogenic bone marrow transplants 7-14 days after transplant
3. Oral manifestations of GvHD are
1. Lichenoid lesions, ulcerations
2. Salivary gland dysfunction
3. Oral sclerosis, trismus

5.3 Immune deficiency
1. Immune deficiency
-Is a defect in the immune system which is primary (intrinsic defect) or secondary to underlying condition
-Presents as SPUR: Suppurative, Persistent, Unusual, Recurrent infections
2. Types of deficiencies
1. Primary antibody deficiency
2. Primary cell-mediated deficiency
3. Primary defects in phagocyte function (quantitative/qualitative)
4. Primary complement deficiency
3. 6 clinical features of immune deficiency disease
1. Recurrent & prolonged infections
2. Clinical features can be minimal despite severe infection
3. Poor response to antibiotics
4. Commonly staphylococcal
5. Involve skin & mucous membranes
6. Complicated by suppurative lympadenopathy
4. Chronic granulomatous disease
-From failure to produce high concentrations of toxic oxygen radicals during the respiratory burst accompanying phagocyte activation
-Chronic granulomatous disease typically presents in 0-3 months as severe skin sepsis caused by S. aureus/ C. albicans
-Complications – hepatic abscess, regional lymphadenopathy, osteomyelitis
-Abscesses & giant cell granulomas

AIDS – caused by HIV type I & II
5. 3 modes of transmission of HIV
1. Sexual intercourse
2. Sharing contaminated needles (needle stick injury)
3. Vertical transmission from mother -> child via breastfeeding/ pre-childbirth
6. Clinical spectrtum of HIV infection
Stage 1 – Transient, acute glandular fever-like smyptoms. In 10-20% of patients after events of infection
2. Asymptomatic
3. Asymptomatic persistent generalised lymphadenopathy (2 or more extra-inguinal nodes enlarged for more than 3 months)
Stage 4. Unexplained lymphadenopathy, diarrhoea, night sweats, systemic symptoms
-Opportunistic infections & tumours (candida)
7. Oral manifestations associated with HIV
1. Candiosis
2. Hairy leukoplakia
3. Kaposi sarcoma
4. Perio
5. NUP & NUG
8. Treatment of HIV – HAART (highly active anti-retroviral therapy) to control viral replication & limit progression of immune deficiency

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