Immunology Part 1 (p102-123- immunodeficiencies, hypersensitivity, modulation) Flashcards
What is reticular dysgenesis?
Failure of stem cells to differentiate along myeloid or lymphoid lineage- failed production of neutrophils, lymphocytes, monocytes/macrophages, platelets.
Fatal in early life unless corrected with transplantation
What is Kostmann syndrome?
Specific failure of neutrophil maturation- autosomal recessive severe congenital neutropenia
Classic form due to mutation in HCLS-1 associated protein X-1 (HAX1)
What is cyclic neutropenia?
Specific failure of neutrophil maturation- autosomal dominant episodic neutropenia every 4-6wks
Mutation in neutrophil elastase
What is leukocyte adhesion deficency?
Neutrophils lack adhesion molecules CD11a/CD18 and CD11b/CD18, which normally bind to ligands on endothelial cells and regulate neutrophil adhesion and transmigration so they fail to exit blood stream
What is leukocyte adhesion deficiency characterised by?
High neutrophil count in blood
Absence of pus formation
Delayed umbilical cord separation
What happens in chronic granulomatous disease?
Absent respiratory burst- deficiency of one of the components of NADPH oxidase and subsequent inability to generate oxygen free radicals that kill intracellular microorganisms
Excessive inflammation- persistent neutrophil and macrophage accumulation so inability to degrade antigens
Which bacteria are people with chronic granulomatous disease particularly susceptible to?
Catalase positive- PLACESS: Pseudomonas Listeria Aspergillus Candida E.Coli Staph aureus Serratia
What result would you see for the nitro-blue tetrazolium (NBT) test in a chronic granulomatous patient and why?
Negative- NBT is a dye that changes colour from yellow to blue following interaction with hydrogen peroxide
How does SCID present generally?
Unwell by 3months of age (protected beforehand by IgG from mother across placenta then colostrum) with: Failure to thrive Persistent diarrhoea Skin disease Graft versus host disease
What mutation is involved in X-linked SCID?
45% of SCID
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1 -> inability to respond to cytokines causes early arrest of T cell and NK cell development and immature B cell production
What causes DiGeorge syndrome and what does it feature?
Deletion at 22q11.2 CATCH 22: Cardiac abnormality (ToF) Abnormal facies- high forehead and low ears Thymic aplasia- T cell lymphopenia Cleft palate Hypocalcaemia/hypoparathyroidism 22- chromosome
How are phagocyte deficiencies diagnosed?
NBT or DHR flow cytometry test
NBT changes from yellow to blue following interaction with hydrogen peroxide
DHR is oxidised to rhodamine which is strongly fluorescent following interaction with hydrogen peroxide
How do you treat phagocyte deficiencies?
Aggressive management of infection
Abx prophylaxis
BMT- definitive
What is treatment for chronic granulomatous disease?
IFN-gamma
What different types of complement deficiency are there?
C1q deficiency
Factor B deficiency
C9 deficiency
SLE
What are the consequences of complement deficiencies?
Increased susceptibility to encapsulated bacterial infections
How are complement deficiencies diagnosed?
CH50 and AP50 tests
How do you treat complement deficiencies?
Vaccination, prophylactic Abx, high levels of suspicion + early treatment, screen family members
What do T cell deficiencies increase the likelihood of?
Viral infections (CMV) Fungal infection (pneumocystitis or cryptosporidium Bacterial infections- esp intracellular organisms (TB, salmonella) Early malignancy
What do antibody deficiencies increase the risk of?
Bacterial infections- staph or strep
Toxins (tetanus, diptheria)
Some viral infections (enterovirus)
How are lymphocyte deficiencies diagnosed?
WCC, lymphocyte subsets, serum Ig and electrophoresis, functional tests
How are T cell deficiencies managed?
Infection prophylaxis and treatment, Ig replacement, BMT gene therapy, thymic transplantation in digeorge syndrome
How are B cell deficiencies managed?
Aggressive tx of infection, Ig replacement every 3 weeks, BMT, immunisation in IgA deficiency
What is a type 1 hypersensitivity disorder, what is it mediated by and what are typical symptoms?
Immediate reaction provoked by re-exposure to an allergen. IgE mediated- mast cells release mediators resulting in vasodilators, increased permeability and smooth muscle spasm
Symptoms:
Angioedema, urticaria, rhinoconjunctivitis, wheeze, d+v, ANAPHYLAXISo
How do you treat atopic dermatitis?
Emollients Skin oils Topical steroids Antibiotics PUVA phototherapy
How do you treat a food allergy?
Dietician
Food avoidance
Epipen
How are most allergies diagnosed?
Skin prick test
What is anaphylaxis?
A severe systemic allergic reaction- respiratory difficulty and hypotension
How do you manage anaphylaxis?
Raise legs, 100% oxygen, IM adrenaline 500mcg, inhaled bronchodilators, hydrocortisone 100mg IV, chlorphenamine 10mg IV, IV fluids
What does a negative skin prick test exclude?
IgE mediated allergy
What is a radioallergosorbent test (RAST) used for?
Measure levels of IgE in serum against a particular allergen (peanut)- confirms dx and monitors response to anti-IgE treatment
Indications- when they can’t stop anti-histamines, anaphylaxis hx or severe eczema
What are component-resolved diagnostics?
It measures IgE response to a specific allergen protein e.g. peanuts contain at least 5 major allergens so it can specifically measure one of them
What is the gold standard for assessing food allergy?
Double blind oral food challenge but risk of severe reaction
What is a useful measure of mast cell activation during an acute allergic episode?
Mast cell tryptase
What is a type II hypersensitivity disorder?
IgG or IgM antibody reacts with cell or matrix associated self antigen. Results in tissue damage, receptor blockade/activation
Name as many type II hypersensitivity disorders as possible (13)
Haemolytic disease of Newborn Autoimmune haemolytic anaemia Autoimmune thrombocytopenic purpura Goodpasture's syndrome Pemphigus vulgaris Graves disease Myasthenia Gravis Acute Rheumatic fever Pernicious anaemia Churg-strauss syndrome Wegener's granulomatosis Microscopic polyangiitis Chronic urticaria
What is the pathology of HDN?
Maternal IgG attack antigens on neonatal erythrocytes
How is HDN treated?
Maternal plasma exchange or exchange transfusion
How do you treat autoimmune haemolytic anaemia?
Steroids
What antigen is involved in autoimmune thrombocytopenic purpura?
Glycoprotein IIb/IIIa on platelets
How is autoimmune thrombocytopenic purpura diagnosed?
Anti-platelet antibody
How is autoimmune thrombocytopenic purpura treated?
Steroids, IVIG, Anti-D antibody, splenectomy
What antigen is involved in Goodpasture’s syndrome?
Non collagenous domain of basement membrane collagen type IV
How is Goodpasture’s syndrome diagnosed?
Anti-GBM Ab
Linear smooth IF staining of IgG deposits on BM
How is Goodpasture’s syndrome treated?
Corticosteroids and immunosupression
What antigen is involved in Pemphigus vulgaris?
Epidermal cadherin
How is pemphigus vulgaris diagnosed?
Direct immunofluorescence showing IgG deposition
How is Graves disease diagnosed?
Anti-TSH R Ab
How do you treat Graves disease?
Carbimazole and propylthiouracil
What antigen is involved in Myaesthenia Gravis?
Acetylcholine receptor
How is myaesthenia gravis diagnosed?
Anti Ach-R Ab and abnormal EMG tensilon test
How do you treat myaesthenia gravis?
Neostigmine
Pyridostigmine
What antigen is involved in acute rheumatic fever?
M proteins on group A strep
How do you treat acute rheumatic fever?
Aspirin, steroids and penicillin
What commonly occur in acute rheumatic fever?
Myocarditis
Arthritis
Sydenham’s chorea
What antigen is involved in pernicious anaemia?
Intrinsic factor and gastric parietal cells
How do you diagnose pernicious anaemia?
Anti-gastric parietal cell Ab, Anti-IF Ab, Schilling test
Treatment for pernicious anaemia?
Dietary B12 or IM
How is Churg-Strauss syndrome (eGPA) diagnosed?
p-ANCA, granulomas, eosinophil granulocytes
How is Churg-Strauss treated?
Prednisolone
Azathioprine
Cyclophosphamide
How is Wegener’s granulomatosis (GPA) diagnosed?
c-ANCA
How is Wegener’s treated?
Corticosteroids
Cyclophosphamide
Co-trimoxazole
How do you diagnose chronic urticaria due to meds, cold, food, insect bites etc?
Challenge test, ESR (raised in urticarial vasculitis) + skin prick test
What is a type III hypersensitivity disorder?
IgG or IgM immune complex (Ab vs soluble Ag) mediated tissue damage
Name some example type III hypersensitivity disorders?
Mixed essential cryoglobulinaemia
Serum sickness
Polyarteritis nodosa (PAN)
Systemic lupus erythematosus (SLE)
What antigen is involved in serum sickness?
Proteins in antiserum (Penicillin)
How is serum sickness diagnosed?
Decreased C3
Blood shows immune complexes or signs of blood vessel inflammation
How do you treat serum sickness?
Discontinue precipitant, steroids, anti-histamines
What antigens are involved in polyarteritis nodosa?
Hep B and Hep C antigens
How is PAN diagnosed?
Clinical criteria, biopsy and ‘rosary sign’
What is a type IV hypersensitivity disorder?
Delayed hypersensitivity. T-cell mediated
Name some examples of type IV hypersensitivity disorders?
T1DM MS Rheumatoid arthritis Contact dermatitis Mantoux test Crohn's
What antigen is involved in T1DM?
Pancreatic beta cell proteins (glutamate decarboxylase)
What antigen is involved in MS?
Oligodendrocyte proteins (myelin basic protein, proteolipid protein)
Diagnosis of MS?
CSF shows oligoclonal bands of IgG on electrophoresis
How do you treat MS?
Corticosteroids
Interferon-beta
Where is the antigen involved in rheumatoid arthritis?
Synovial membrane
How do you diagnose rheumatoid arthritis?
X-ray
Rheumatoid factor (85% sensitive)
Anti-CCP (95% specific)
Raised ESR and CRP
How do you treat rheumatoid arthritis?
Analgesia
Steroids
DMARDs
How do you treat crohn’s?
Antibiotics
Anti-inflammatory drugs e.g. mesalazine, TNF alpha antagonists e.g. infliximab or steroids
What is limited cutaneous scleroderma?
CREST syndrome:
Calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia
How is limited cutaneous scleroderma (CREST) diagnosed?
Anti-centromere antibodies
What is difference between limited and diffuse cutaneous scleroderma?
Limited- CREST
Diffuse- CREST + GIT + interstitial pulmonary disease + renal problems
Antibodies- anti-topoisomerase, RNA pol I, II, III, fibrillarin
What symptoms are there in Sjogren’s syndrome?
Dry mouth, eyes, nose and skin
May affect kidneys, vessels, lungs, liver, pancreas and PNS
What antibodies are present in Sjogren’s?
Anti-Ro and anti-La
What is IPEX syndrome?
Immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance syndrome
Most affected children die within 2y- BMT only cure
Which HLA serotypes are associated with coeliac disease?
DQ2 or DQ8
28 or not to eat, that is the question
Gold standard for coeliac diagnosis?
Duodenal biopsy (not 1st line)
What does Human Normal Immunoglobulin (antibody replacement) treatment consist of and what is it used for?
Preformed IgG from donors against full range of organisms given every 3-4w
Used for: Primary antibody deficiencies (CVID, Brutons etc) Secondary deficiencies (CLL and multiple myeloma post BMT)
What is specific immunoglobulin (passive vaccination) treatment used for?
Post-exposure prophylaxis with Ig specific to rabies, varicella zoster, Hep B and tetanus
Derived from plasma donors with high IgG titres of specific Ab
What is the aim and what involves the use of interferons (recombinant cytokines)?
Boost immune response to cancer and some pathogens e.g:
Interferon alpha used for Hep C, Hep B, Kaposi’s, hairy cell leukaemia, MM
Interferon beta used for relapsing MS, Bechets
Interferon gamma- chronic granulomatous disease
How do iplimumab and pembrolizumab/nivolumab work?
They block immune checkpoints
Iplimumab is an antibody specific for CTLA4 so blocks downregulatory immune checkpoint and allows T cell activation- used in advanced melanoma
Pembrolizumab/nivolumab are an antibody specific for PD-1 which works in same way as iplimumab
What types of immunosuppresive therapy are there?
Anti T cell monoclonal antibodies Anti proliferative agents Inhibitors of cell signalling Corticosteroids Anti TNFa monoclonal antibodies Plasmapheresis
How do corticosteroids suppress the immune system?
They inhibit phospholipid A2 which blocks arachidonic acid, reduces prostaglandin synthesis, inhibits phagocyte trafficking and release of proteolytic enzymes, lymphopenia, promotes apoptosis, blocks cytokine gene expression and decreased Ab production
When are corticosteroids used to suppress the immune system?
Auto-immune disease, auto-inflammatory disease, prevention and treatment of transplant rejection
Name some examples of anti-proliferative agents
Cyclophosphamide
Mycophenolate mofetil
Azathioprine
Methotrexate
How does cyclophosphamide suppress the immune system?
Alkylates the guanine base of DNA and damages it, preventing cell replication. Affects B cells > T cells
When are cyclophosphamides used?
CTD, vasculitis, anti-cancer agent
How does mycophenolate mofetil work?
Inhibits IM PDH, prevents guanine synthesis so blocks de novo nucleotide synthesis and prevents replication of DNA
When is mycophenolate mofetil and azathioprine used?
Transplantation, auto-immune diseases and vasculitis
How does azathioprine work?
Anti-metabolite agent. Metabolised by liver to 6-mercaptopurine, blocks de novo purine synthesis- prevents DNA replication, preferentially inhibits T cell activation and proliferation
How does methotrexate work?
Inhibits dihydrofolate reductase (DHFR) therefore decreases DNA synthesis
When is methotrexate used?
RA, psoriasis, crohn’s, chemo and abortifacient
How does plasmapheresis work?
Plasma is treated to remove immunoglobulins and then reinfused
When is plasmapheresis used?
Severe antibody-mediated disease (Goodpastures, MG, vascular rejection)
Name some examples of cell signal inhibitors?
Tacrolimus Cyclosporin Sirolimus Tofacitinib Apremilast
How do tacrolimus and cyclosporin work and when are they used?
Inhibit calcineurin which normally activates transcription of IL-2 hence reduces T cell proliferation
Used in rejection prophylaxis for transplants
How does tofacitinib work and when is it used?
Inhibits JAK in RA
How does apremilast work and when is it used?
PDE4 inhibitor in psoriasis and PA
Name some immunosuppressive agents that target cell surface antigens?
Basiliximab Abatacept Rituximab Natalizumab Tocilizumab Muromonab-CD3 Anti-thymocyte globulin Daclizumab Efalizumab Alemtuzumab
Name some immunosuppressive agents that target cytokines?
Infliximab Adalimumab Certolizumab Golimumab Etanercept Denosumab
What is allergen desensitisation?
Supervised admin of allergen- tiny dose which is escalated every week- good for bee and wasps, grass pollen, house dust mite but not food or latex
