immuno Flashcards
PD-1 inhibitor
work by disrupting the binding of PD-1 on tumour cell
–> T cell programmed cell death
mtor inhibitors
prevent autonomous activity of the mtor pathway
ctla4 inhibitors
enhance ability if APCs to activate T cell
HIV-2
– less virulent – lower viral load – lower rates of vertical transmission – slower progression – HIV-2 is less virulent. – Seen mainly in western central Africa and southern and western India.
peripheral neuropathy - HAART
Didanosine, Stavudine and Zalcitabine
hypersensitivity types
Type 1: Specific IgE on mast cell ie: anaphylactic reaction to penicillin.
Type 2: IgG cytotoxic ie: hemolytic anemia
Type 3: Immune complex ie: serum sickness,GN
Type 4: T cell mediated ie: contact dermatitis
most powerful prediction from HIV to AIDS
CD4 count
strongest single predictive marker of disease progression at all stages of HIV
CD38 expression by CD8 cells
protease inhibitor s/e
- NAVIR
- lipodystrophy
- ritoNAVIR
- saquinavir
- nefinavir - increased risk of MI
HAART teratogenic
efavirenz
HIV cx
CD4 >200
-herpes zoster (CD 4: 200-500)
CD4 <200
- oral candidiasis
- HSV
- hairy leukoplakia
- crytosporidosis
- toxoplasmosis
Heterozygosity for CCR Delta 32 in HIV
slower disease progression to AIDS by two fold
HLA-B5701
abacavir hypersensitivity reaction
- avoid Abacavir
atazanavir
indirect hyperbili
Absolute contraindication to Protease inhibitors (CYP 3A4 inhibitor)
- Cisapride- torsades.
- Lovastatin- rhabdomyolysis ** (metabolised by CYP 3A4) –> can use pravastatin
- Midazolam-prolonged sedation
abacavir
MI (90%)
Immune reconstitution sydrome (IRIS)
symptoms include:
-high fever, increase in LN, worsened CNS lesion, worsened pulmonary infiltrate, increased pleural effusion
Rx: NSAIDS for symptom relief.
CONTINUE TB therapy and ART!!
hep b rx in HIV and Hepatitis B co-infection
For patient who require HBV treatment:
Not yet on HAART:
Truvada (Emtricitabine + tenofovir) + N-NRTI or PI
If on HAART, 2 options:
1. Lamivudine naive:
– Truvada or Lamivudine + tenofovir.
– Entecavir only if patient has full suppression of HIV
- On Lamivudine:
– Add tenofovir or adefovir
– Or change to Truvada.
opportunistic infection occurs at all CD4 cell counts
Pneumococcal pneumonia and TB
T helper cells
Th1 secrete IFN-γ, TNF, Lymphotoxin (Defence against intracellular pathogen)
Th2 secrete IL-4,IL-5,IL-6,IL-10,IL-13,TGF-β (Defence against Helminths)
Th17 secrete IL-17 (Defence against candida and staph)
MHC
Class I– Intracellular proteins.Presents peptide to CD8 T cell.
Class II- extracellular proteins.Presents peptide to CD4 T cell.
Types of T cells
Helper
– T- helper cells known as CD4+ T cells because they express the CD4 protein on their surface.
– Activated when presented with peptide antigen by MHC class II expressed on APC.
– Once activated, they divide and secrete cytokines
– Can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17,
Cytotoxic
– Cytotoxic T cells destroy virally infected cells and tumor cells, and implicated in transplant rejection.
– Also known as CD8+ T cells
– Recognize their targets by binding to antigen associated with MHC Class I.
Memory
– Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved.
– Expands to large numbers of effector T cells upon re-exposure to their cognate antigen.
– Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells).
– Memory cells may be either CD4+ or CD8+.
– Memory T cells typically express the cell surface protein CD45RO.
Regulatory
– Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance.
– Main role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus.
– Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells.
– Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus,
– Adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3.
– Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.
Natural killer
– NKT cells recognize glycolipid antigen presented by a molecule called CD1d
– Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules).
– They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses.
γδ
– γδ T cells (gamma delta T cells) represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface.
– A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain.
– This group of T cells is much less common (2% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).
– γδ T cells are not MHC restricted and seem to be able to recognize whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells.
coeliac dis
HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium
IL 1
- produced by macrophage,monocytes and dendritic cells.
- critical for inflammatory response against infection.
- Reset the hypothalamus thermoregulatory center causing fever.
IL 2
induces proliferation of T-cells.
IL 3
Hematopoietic lymphoid growth and proliferation
IL 4
acts on B-cells to promote IgE switching
-Overproduction of IL-4 assoc with allergies
IL 5
regulates eosinophil growth and activation
IL 6
differentiation of activated B-cells to plasma cells
IL 8
Neutrophil chemotaxis
IL 11
stimulates megakaryocytopoiesis to produce platelets
PAMPs assoc pathogens
Bacterial: Peptidoglycan Bacterial DNA Lipoteichoic acids (Gram positive) Lipopolysaccharides (Gram negative)
RNA viruses:
dsRNA
Yeast:
Mannans.
absence of B cells
X-linked agammaglobulinaemia (Bruton’s disease)
T cell immunodeficiencies
1) Idiopathic CD4 lymphopenia
2) Chronic mucocutaneous candidiasis
3) Hyper-IgE syndrome
X linked SCID
Deficiency of cytokine receptor γ common chain
Autosomal recessive SCID: Jak 3 deficiency IL-7Rα deficiency ZAP 70 defieiency CD3 deficiency RAG-1,2 deficiency Myeloid or reticular dysgenesis.
Disorders of neutrophil phagocytic function
1) Chronic granulomatous disease
2) Leukocyte adhesion deficiency
3) Chediak-Higashi Syndrome
4) Neutrophil enzyme deficiency-G6PD,MPO
NOD-like receptor group responsible for the acute inflammation seen in gout
NALP 3
-Monosodium urate crystals(MSU) and Calcium pyrophosphate dihydrate(CPPD) activates the NALP3 inflammasome
Dendritic cells function
– superb APC
– Lurks in tissues as sentinels.
– Activates quiescent naive and memory T(Th,Tc) and B cells.
– Highly potent activators even with low levels of antigen.
– Two distict types: conventional(cDCs) and plasmacytoid(pDC)
Plasmacytoid DC expresses TLR7(RNA virus) and TLR9(DNA virus) in endosomes and induces rapid anti-viral state.
Hereditary Angioedema
-deficiency of C1 inhibitor leading to continuous activation and consumption of C4 and C2.
– C2 is responsible for kinin release that results in vasodilation and increased vascular permeability leading to angioedema.
Clinical presentation:
– Typically school age.
– Recurrent edema that is non pruritic, painless, non whealing and usually resolves within 72 hours.
– Edema can be cutaneous,laryngeal and abdominal (mimics acute abdomen-early diagnosis may avoid unnecessary surgery!!)
Treatment:
- C1-inhibitor concentrate.
- Danazol if frequent attacks
- Tranexamic acid
- ε-aminocaproic acid
APC
External antigen: dendritic cell, macrophage, B-cell (express MHC II)
Internal antigen: All MHC class I positive cells (express MHC I)
serum beta 2 microglobulin
component of the HLA class I molecule -Clinically relevant in reflecting cell turnover
Prognosis in Multiple myeloma and HIV.
-The higher the worse.
Serum tryptase
Tyrptase helpful if collected within 3 hours of IgE mediated reaction.
Used to distinguish mast cell dependent anaphylaxis from other systemic event.
Does NOT differentiate between IgE and non-IgE mediated causes.
most specific for the diagnosis of NSAIDs hypersensitivity
Basophil activation test
acute phase reaction
-IL-1, IL-6 and IL-8, and TNF-α
Positive acute phase proteins (Increase in inflammation):
- C-reactive protein,
- Mannose-binding protein,
- complement factors,
- ferritin,
- ceruloplasmin,
- Serum amyloid A and
- haptoglobin.
- serpins.
- Alpha 2-macroglobulin
Negative acute phase protein (decrease in inflammation): mnemonic “ATTTRA”.
- albumin,
- transferrin
- transthyretin
- transcortin
- retinol-binding protein
- antithrombin
IgG4-positive multiorgan lymphoproliferative syndrome
Characteristic features of IgG(4)+MOLPS are as follow:
1) Serum IgG4 is prominently elevated,
2) IgG4-positive plasma cells infiltrate in involved tissues
3) various mass-forming lesions with fibrosis develop in a timely and spatial manner
4) good response to corticosteroids.
5) no positivity of anti-SS-A/SS-B antibodies
Organ system affected by IgG(4)+MOLPS:
1) autoimmune pancreatitis
2) lacrimal and salivary gland (Mikulicz’s disease)
3) retroperitoneal fibrosis
4) IgG4-associated nephropathy
CTLA 4
generates a NEGATIVE signal
-Stimulating CTLA4 –> Block the immune response
Anti-CTLA4 stimulates the immune response by blocking CTLA4
hereditary angioedema mx
Acute management includes:
1) C1-INH concentrate from donor blood
2) FFP if in emergency as FFP contains C1-INH.
3) Kallikrein inhibitor (Ecallantide)- inhibits plasma kallikrein.
4) Bradykinin inhibitor (Icatibant)- inhibits bradykinin B2 receptor.
Prophylaxis:
1) Danazol- Androgens increase production of C1-INH in the liver.
2) Tranexamic acid- fibrinolysis inhibitors
The condition does NOT respond to antihistamines, corticosteroids, or epinephrine.
HLA
HLA Class I:
- HLA- A, B, C (E,F,G,H)
HLA Class II:
- HLA- DR, DP, DQ(DM and DO)
HLA-DR alpha chain is invariant (unchanged) while HLA-DR beta chain is very polymorphic.
Some disease associations:
Ankylosing spondylitis HLA B27
Rheumatoid arthritis HLA DR4
Autoimmune conditions (SLE, Addisons, Type 1DM, Grave’s, Myasthenia) HLA DR3.
Transplant and HLA:
– Acute graft rejection caused by cross reactivity of T cell receptors for foreign MHC.
Types of hypersensitivity
Type I – Anaphylactic
- antigen reacts with IgE bound to mast cells
- anaphylaxis, atopy
Type II – Cell bound
- IgG or IgM binds to antigen on cell surface
- autoimmune haemolytic anaemia, ITP, Goodpasture’s
Type III – Immune complex
- free antigen and antibody (IgG, IgA) combine
- serum sickness, systemic lupus erythematosus, post-streptococcal glomerulonephritis, extrinsic allergic alveolitis (especially acute phase)
Type IV – Delayed hypersensitivity
- T cell mediated
- tuberculosis, tuberculin skin reaction, graft versus host disease, allergic contact dermatitis, scabies, extrinsic allergic alveolitis (especially chronic phase)
In recent times a further category has been added:
Type V – Stimulated hypersensitivity
- IgG antibodies stimulate cells they are directed against
- Graves’, myasthenia gravis
