The main cause of renal allograft loss (excluding patient death with a functioning graft) is...
The most commonly transplanted solid organ is...
Target of tacrolimus
Drugs targeting calcineurin
Immunosupressive drugs targeting the cell cycle
Signs and symptoms of GVHD
Skin: Rash Gut: Nausea, vomiting, abdominal pain, diarrhoea, bloody stool Liver: Jaundice
Treatment of GVHD
Clinical features suggesting primary immune deficiency
Two major or one major and recurrent minor infections in one year Unusual organisms Unusual sites Unresponsive to oral antibiotics Chronic infections Early structural damage Family history Failure to thrive Skin rash (eczema) Mouth ulceration Chronic diarrhoea
List constitutive barriers to infection provided by skin
Keratin cells: tightly packed. Limit colonisation
Low oxygen tension
Low pH: due to secretions
Sebaceous glands: Produce hydrophobic oils to repel water and microorganisms
Produce lysozyme which destroys srtructural integrity of cell walls
Produce defensins: small cationic proteins that form pore like microbial membrane defects
Sweat glands: produce a watery fluid containing ammonia, and lactic acid
List constitive barriers to infection provided by mucosal surfaces
Physical barrier to trap invading pathogens
Secretory IgA prevents bacteria and viruses attaching to and penetrating epithelial cells.
Lysozyme and antimicrobial peptides directly kill invading pathogens.
Lactoferrin acts to starve invading bacteria of iron (and has a direct antimicrobial effect)
Cilia: Cilia directly trap pathogens and contribute to removal of mucous, assisted by physical manoeuvres such as sneezing and coughing.
List the cells and soluble components of the innate immune system
Cells Polymorphonuclear cells – neutrophils, eosinophils, basophils Monocytes and macrophages Natural killer cells Dendritic cells Soluble components Complement Acute phase proteins Cytokines and chemokines
Names of specialised macrophages in different tissues: Liver Kidney Bone Spleen Lung Neural tissue Connective tissue Skin Joints
Liver Kupffer cell Kidney Mesangial cell Bone Osteoclast Spleen Sinusoidal lining cell Lung Alveolar macrophage Neural tissue Microglia Connective tissue Histiocyte Skin Langerhans cell Joints Macrophage like synoviocytes
Examples of opsonins
Antibodies Complement components Acute phase proteins such as CRP
Reactive oxygen species used in oxidative killing
Hydrogen peroxide Superoxide (O2-)
Enzyme that produces reactive oxygen species used for oxidative killing
Types of recurrent infections caused by phagocyte defiencies
SKIN AND MOUTH Recurrent deep bacterial infections: Staphylococcus aureus
Mycobacteria: MTB and atypical
Recurrent fungal infections: Candida albicans Aspergillus fumigatus and flavus
Primary immune deficiencies characterised by failure to produce neutrophils (Name and mutation/protein affected)
Failure of stem cells to differentiate along myeloid or lymphoid lineage Reticular dysgenesis – autosomal recessive severe SCID: mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
Specific failure of neutrophil maturation Kostmann syndrome - autosomal recessive severe congenital neutropenia: classical form due to mutation in HCLS1-associated protein X-1 (HAX1)
Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks: mutation in neutrophil elastase (ELA-2) NOTE: ELA-2 now known as ELANE
Primary immune deficiencies characterised by failure of leukocyte migration (Name and mutation/protein affected)
Leukocyte adhesion deficiency: Deficiency in CD11a/CD18 and CD11b/CD1. In LAD1 (the more common variant) the defiency is in the Beta-2 integrin subunit (CD18) In LAD2 fucosylated carbohydrate ligands for selectins are absent. This is rarer and causes severe growth restriction and mental retardation In LAD 3 activation of all beta integrins (1, 2, and 3) is defective
Primary immune deficiencies characterised by failure of oxidative killing (Name and mutation/protein affected)
Chronic granulomatous disease Deficiency in one of the components of NADPH oxidase
Nitroblue tetrazolium (NBT) test and Dihydrorhodamine (DHR) flow cytometry test, test for the presence of... and therefore assess....
Hydrogen peroxide Ability of a cell to produce reactive oxygen species
a) Cytokines important in oxidative killing of mycobacteria b) Briefly describe the pathway
a) IFN gamma and IL12 b) Infected macrophages stimulated to produce IL12 IL12 induces T cells to secrete IFNg IFNg feeds back to macrophages & neutrophils Stimulates production of TNF Activates NADPH oxidase Stimulates oxidative pathways
Investigation of Kostmann syndrome Neutrophil count: Leukocyte adhesion markers: Nitroblue test: Pus: Deficiency: Problem:
Neutrophil count: Absent Leukocyte adhesion markers: Normal Nitroblue test: Absent Pus: No Deficiency: HCLS1-associated protein X-1 (HAX1) Problem: Maturation of neutrophils leading to congenital neutropenia
Investigation of Leukocyte adhesion deficiency Neutrophil count: Leukocyte adhesion markers: Nitroblue test: Pus: Deficiency: Problem:
Neutrophil count: Increased during infection Leukocyte adhesion markers: Absent Nitroblue test: Normal Pus: No Deficiency: deficiency in CD11a/CD18 and CD11b/CD18 Problem: Inability of leukocytes to leave the bloodstream due to lack of adhesion molecules.
Investigation of chronic granulomatous disease Neutrophil count: Leukocyte adhesion markers: Nitroblue test: Pus: Deficiency: Problem:
Neutrophil count: Normal Leukocyte adhesion markers: Normal Nitroblue test: abnormal Pus: Yes Deficiency: Any of the components that make up NADPH oxidase Problem: Absent respiratory burst leading to failure of oxidative killing. Persistent infection and inflammation. Granuloma formation. Lyumphadenopathy and hepatosplenomegaly
Treatment of Kostmann syndrome
G-CSF, prophylactic antibiotics. BMT if G-CSF if ineffective
Treatment of leukocyte adhesion deficiency
Depends on severity. LAD1: good hygiene especially oral hygiene. Systemic antibiotics guided by culture and sensitivity for acute infections. BMT used for severe phenotype. LAD2: antibiotic treatment usually effective for acute infections. Can use prophylaxis if infections recurrent. (Children afflicted with multiple other issues). LAD3: BMT, needs to be in early infancy.
Treatment of chronic granulomatous disease
Antibiotic prophylaxis: Septrin Antifungal prophylaxis: itraconazole Interferon gamma prophylaxis Aggressive treatment of infections Treat inflammatory manifestations e.g. glucocorticoids
Natural killer cells are...
Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity
Complement proteins are produced by..
Formation of antigen-antibody complexes activates which complement pathway? Starts with which protein?
Classical C1 (conformational change)
Describe initiation of the MBL complement pathway
MBL: mannose binding lectin. Produced by the liver in response to infection. Binds to carbohydrates found on many pathogens including multiple bacteria, viruses and yeasts. In blood MBL is complexed with another protein (MASP). MASP has enzymatic activity and cleaves C4 into C4a and C4b. C4b binds to the pathogen and starts the process forming C3 convertase.
Roles of fragments released during complement activation pathway
Punch holes in bacterial membrabes Increases vascular permeability and cell trafficking to site of inflammation Solubilise and clear immune complexes Promotes mast cell/basophil degranulation Activates phagocytes Opsonisation of pathogens to promote phagocytosis
Complement deficiency increases risk of which type of infection
Neisseria meningitides (Meningococcus) Streptococcus pneumoniae (Pneumococcus) Group B streptococcus Haemophilus influenza Specifically if alternative/terminal pathway are involved.
Deficiency in components of classical complement pathway increases risk of... Why?
SLE: The classical pathway clears necrotic and apoptotic cells. Failure leads to build up of self antigens especially nuclear components. This leads to increased risk of autoimmunity Also complement activation increases clearance of immune complexes by erythrocytes. Deficiency leads to build up in joints, skin and kidneys and resulting local inflammation. Infection: Immune complexes fail to trigger complement
Most common complement deficiency seen in SLE
MBL deficiency leads to...
Increased infection in patients who have another cause of immune impairment Premature infants Chemotherapy HIV infection Antibody deficiency
Deficiency in alternative complement pathway factors leads to...
Increased risk of infection with encapsulated bacteria
Factors involved in alternative complement pathway
Factor B Factor I Factor P
Consequences of C3 deficiency
Severe susceptibility to bacterial infections Especially encapsulated bacteria as unable to lyse encapsulated bacteria Increased risk of development of connective tissue disease
List secondary causes of complement deficiency
Active lupus: persistent production of immune complexes leading complement consumption Nephritic factors: autoantibodies targeted at complement components. Stabilise C3 convertase leading to consumption of C3
Two types of functional complement tests
CH50 classical pathway AP50 alternative pathway
Management of complement deficiencies
Vaccination Boost protection mediated by other arms of the immune system Meningovax, Pneumovax and HIB vaccines Prophylactic antibiotics Treat infection aggressively Screening of family members
Role of CCR7
Found in lymphatic tissue. Important role in directing dendritic cells to lymph nodes. CCL19 and CCL21 are ligands for CCR7
Ligands for CCR7
Brief pathogenesis of coeliac disease
Peptides from gliadin are deamidated by tissue transglutaminase (enzyme) and presented by APC CD4 T cells recognise these deamidated peptides presented by HLA DQ2 or DQ8 (possibly after an innate immune system trigger) CD4 T cell activation results in secretion of IFN-gamma and may indirectly lead to increased IL-15 secretion IL-15 promotes activation of the intra-epithelial lymphocytes (IEL) (Cells within the gut) Intra-epithelial lymphocytes kill epithelial cells in an NKG2D (expressed on NK cells) dependent manner The activation and function of the intra-epithelial lymphocytes appears to be independent of engagement of their T cell receptor B cell with surface receptors for gliadin interact with the T cells. B cells mature and start producing Abs against gliadin. T cells specific for gliadin provide help for B cells whose surface receptors recognise the transglutaminase part of the transglutaminase / gliadin complex. These mature and produce Abs against transglutaminase. (antibodies also produced against endomysial cells)
First line immunological test for coeliac in most labs
Anti-transglutaminase antibodies (IgA) (but disappears within several months of gluten free diet, IgG anti-gliadin persists for upto 12 months).
Gold standard test for coeliac
Duodenal histology remains the “gold standard”
Villous atrophy and crypt hyperplasia Increased lymphocytes in villi
Type of reaction caused by transfusion of incompatible blood (not ABO incompatibility)
EXTRAVASCULAR HAEMOLYSIS in the spleen – a delayed haemolytic transfusion reaction
Cause of an immediate transfusion reaction
Plasma from the lab takes... minutes to thaw
Compatibility required for plasma transfusion
Give ABO compatible but D group doesn't matter AB plasma can be given to all groups as it has no RBC antibodies but it is in short supply No need to cross match
Compatibility required for blood transfusion
Give ABO/D compatible Consider special requirements
Compatibility required for platelet transfusion
ABO/D antigens weakly expressed Should be D compatible No need to cross match If group O given to A, B or AB patients select ‘high-titre’ negative
Blood transfusion (red cells): ...will typically give a Hb increment of...
In acute blood loss, transfusion is indicated if patient has lost more than...% of blood volume
Irradiated blood is required for...
highly immunosupressed patients at risk of engraftment of donor lymphocytes to prevent transfusion associated graft versus host disease (TA-GvHD)
CMV negative blood is only required for....
intra-uterine and neonatal transfusions (new guidance 2012). Also for elective transfusion in pregnant women (baby in-utero is exposed to maternal transfusion)
Auto-inflammatory diseases are caused by...
Genetic abnormality affecting the innate immune system, often in a site-specific manner
Immunopathology is caused by
May describe damage resulting from the immune response to ongoing infection
Autoimmune disease is caused by...
Genetic abnormality affecting the adaptive immune system and is often associated with presence of auto-antibodies
Monogenic auto-inflammatory diseases commonly affect which cytokines?
IL1 and/or TNF
Name 2 monogenic autoinflammatory disorders
TRAPS (TNF receptor associated periodic syndrome) Familial mediterranean fever
Draw the inflammasome complex
Describe pathway affected by calcineurin inhibitors
Outline the the classification of vasculitis and give examples from each class
Examples of infections seen in different types of immunodeficiency