Hypersensitivity Types 1-4
|Type 1||immediate(mins), IgE mediated response to an antigen in a previously sensitised host||vasoactive agents and cytokines released for acute inflammation- oedema, smooth muscle spasm, mucus production||allergy, anaphylaxis|
|Type 2||delayed type, antibody formed against an antigen that is on cell surface or ECM||The IgG and IgM Ab causes phagocytosis(opsonisation, Fc receptor, Complement), cell lysis by activated complement(MAC) or dysfunction. Leukocyte recruitment/fc inflammation. ADCC||Auto immune haemolytic anaemia, good pastures syn, Graves disease, Myasthenia gravis, Rheumatic heart disease, glomerulonephritis, Tx reaction|
|Type 3||delayed type, antigen-antibody complexes are formed that deposit in tissues||cause inflammation via complement–> recruit Leukocytes, produce toxic metabolites and enzymes||post strep glomerulonephritis, SLE, Arthurs disease, Serum sickness(systemic), joints|
|Type 4||delayed type, T cell mediated inflammation||Cytotoxic t cells and activated macrophages–> perivascular cellular infiltrates, oedema, cell destruction, granuloma||TB, transplant rejection, Multiple sclerosis, T1DM, contact dermatitis, RA|
- Type I
- Immediate – vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions. These changes usually become evident within 5 to 30 minutes after exposure to an allergen and tend to subside in 60 minutes.
- In many instances (e.g., allergic rhinitis and bronchial asthma), a second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. This late- phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage.
- Direct pathway
- APC on graft have high density of MHC II with the foreign antigen in them which stimulate host CD8 cell+++
- Host T cells also recognise the donor tissue as having foreign proteins in their MHC I
- Both lead to T cell activation, first more so –> Activated (costimulators)–> cell death, increased vasc permeability, endothelial injury –> important in acute rejection
- Indirect pathway
- APC of Host –> donor protein on MHC II –> CD4 cell –> increased IF gamma –> increase activated macrophages, MHC presentation, B cells–> plasma cells –> Abs -> endothelial injury –> seen in chronic or late acute rejection.
- Amplitude of rejection depends on level of genetic disparity – HLA incompatibility gives strong rejection
- Speed increases with increasingly vascularised tissues.
- 25% chance that siblings have identical HLA – because you inherit HLA genes and express from both parents
- Sensitisation then effector stage
Stages of rejection
- the transplanted tissue is rejected within minutes to hours because vascularization is rapidly destroyed.
- the recipient has preexisting antibodies against the graft, which can be induced by prior blood transfusions, multiple pregnancies, prior transplantation, or xenografts against which humans already have antibodies.
- The antigen-antibody complexes activate the complement system, causing massive thrombosis in the capillaries, which prevents the vascularization of the graft.
- The kidney is most susceptible to hyperacute rejection; the liver is relatively resistant
- Manifests in first 6mo
- Direct pathway via donor dendritic cells becoming APC and activating cellular immunity esp in lymphoid tissues
- Indirect pathway via Ab and complement. Can occur in first week
- Months to years
- Antibody and cell mediated
- Manifests as fibrosis in the grafts eg accelerated CAD, bronchiolitis obliterans, vanishing bile ducts, glomerulopathy
Graft vs host disease
Passenger immunocompetent T lymphocytes on graft recognise host as foreign and begin attacking, host has weak immune system
- Acute GVHD
- Dermatitis – pruritic or painful
- Hepatitis – itch
- Enteritis – diarrhoea, interstinal bleeding, cramps, ileus
- Within 100 days after allogeneic hematopoietic-cell transplantation (HCT).
- Chronic GVHD describes a more diverse syndrome developing after day 100.
- Ocular– Burning, irritation, photophobia, and pain from lack of tear secretion
- Oral and GI– Mouth dryness, sensitivity to acidic or spicy foods, dysphagia, odynophagia, and insidious weight loss
- Pulmonary– Obstructive lung disease, with symptoms of wheezing, dyspnea, and chronic cough that is usually nonresponsive to bronchodilator therapy
- Neuromuscular– Weakness, neuropathic pain, and muscle cramps
- High risk of GVHD
- Allogenic HCT
- transplantation of solid organs containing lymphoid tissue
- transfusion of unirradiated blood products.
Auto-immune diseases: Know some for MCQs
SLE:- know the major clinical manifestations.
- Relapsing and remitting disease – affects mainly women and starts in child bearing age.
- Classic triad – fever, joint pain and rash
- Symptoms- relapsing and remitting
- malaise, fatigue, myaligia, fever
- LN, weight loss, Alopecia, nail fold infarcts, Reynaud’s, non infective endocarditis, stroke, migraine, retinal exudates.
- Sulphonamides and OCP may worsen symptoms.
- Ix- CDE
- C3 and C4 levels(should be down)
- Anti dsDNA titres(high)
- ESR(raised, CRP normal),
- We offer a mnemonic that contains the 11 categories used by the American College of Rheumatology, from which four or more must be present to diagnose
SLE: A RASH POINts MD.
- Renal disease (proteinuria, cellular casts)
- ANA (positive antinuclear antibody)
- Serositis (pleurisy or pericarditis)
- H aematological disorders (haemolytic anaemia or leucopenia or lymphopenia or thrombocytopenia)
- Oral ulcers
- I mmunological disorder (positive LE cell, anti-DNA, anti-Sm, false positive serological test for syphilis)
- N eurological disorders (seizures or psychosis, in the absence of other causes)
- Malar rash
- Discoid rashBecause the malar rash is the most easily recalled finding, this mnemonic uses that word and an accompanying message that it “points an MD to a possible diagnosis.”
Immunodeficiency syndromes: 1′ vs. 2′. What types of immune deficiency are you aware of ?
- X-linked agammaglobulinemia (XLA)
- severe combined immunodeficiency (SCID disorders)
- common variable immunodeficiency
- Alymphocytosis (“boy in a bubble” disease)
- Immunologic cancers eg leukaemia, multiple myeloma
- Severe burn
HIV / AIDS:
- Risk groups
- Multiple sex partners
- Unprotected sex
- Health care workers – needle stick injury
- Mother to child – intrapartum and breastfeeding
- Blood Tx before 1985
- Viral structure
- HIV – 1 and HIV -2: Lentivirus(retrovirus)
- enveloped, diploid, single-stranded, RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA.
- Mechanism of immunopathogenesis.
- Infect and kill CD4 cells when replicating
- Infected CD4 cells recognised and killed by other T cells
- Activation of noinfected CD4 cells –> activation induced apoptosis
- Major abnormalities of immune function
- Dysregulation of B cell Ab production
- Altered activity of macrophages and monocytes
- Increase in CD8: CD4
- Opportunistic infections, more viral and fungal than bacterial.
- Natural history
- 2-8wks acute HIV syndrome
- Asymptomatic or flu-like illness during seroconversion – fever, malaise, generalised rash.
- Asymptomatic HIV infection
- Constitutional Sx
- AIDS defining illness – CD4 <200
- Clinical features.
- Recurrent, severe opportunistic infections in an otherwise healthy person
- Generalised lymphadenopathy
- Wt loss
- Candida, genital herpes
- AIDS-defining illnesses:
- Cancers – cervical, lymphomas
- Pneumocystic Jerovici
- Herpes simplex