Immunology Flashcards
What factors make up the adaptive immune system?
B lymphocytes
T lymphocytes
What are categories of primary immunodeficiency?
Phagocyte deficiencies (innate cell-mediated immunity) Complement deficiencies (innate humoral immunity) Severe combined immuno-deficiencies (adaptive cell-mediated immunity) Predominantly antibody deficiencies (adaptive humoral immunity)
What are categories of secondary immunodeficiency?
Hyposplenism / Asplenism
Haematological malignancies
HIV / AIDS
What can cause Immunosuppression?
Steroids & other immunosuppressive drugs Cytotoxic chemotherapy (for malignancies)
What factors make up the innate immune system?
Epithelial barriers Phagocytes Dendritic cells Complement Acute phase proteins NK cells
What is Chronic Granulomatous Disease (CGD)?
Multiple possible defects (most frequently X-linked)
Phagocytes unable to destroy ingested microbes due to a lack of oxidative burst to produce free radicals
Excessive granuloma formation occurs instead
What are clinical features of chronic granulomatous disease?
Eecurrent & persistent infections: pneumonia, skin infections, abscesses (skin & internal), septic arthritis and osteomyelitis
What investigations can be used to diagnose chronic granulomatous disease?
Nitroblue-tetrazolium (NBT) test: microscopy (normal phagocytes reduce NBT to a dark pigment)
Dihydrorhodamine (DHR) test: flow cytometry (normal phagocytes reduce DHR to a fluorescent pigment)
Genetic analysis to identify exact genetic defect
What are treatment options for chronic granulomatous disease?
Early diagnosis and treatment of any infections
Prophylactic antibiotics (co-trimoxazole and imidazoles)
Recombinant IFN-gamma (70% less infections)
Bone marrow / stem cell transplantation (curative)
Describe the process of phagocytosis
Chemotaxis and adherence of microbe to phagocyte
Ingestion
Formation of a phagosome
Fusion of phagosome with a lysosome to form phagolysosome
Digestion of ingested microbe by enzymes
Formation of residual body containing indigestible material
Discharge of waste materials
What is Common Variable Immunodeficiency (CVID)?
Multiple possible defects (not X-linked)
Hypogammaglobulinaemia (IgG, usually IgA, possibly IgM)
Lack of antibodies to neutralise & opsonise pathogens
Severe, persistent, unusual and recurrent infections, autoimmune, malignant, enteric and lymphoid disorders
What are clinical features of common variable immunodeficiency?
Streptococcus pneumoniae (LRTIs and sepsis)
Haemophilus influenzae (URTI/LRTIs and meningitis)
Neisseria meningitidis (meningitis)
Otitis media (Pseudomonas)
Bronchiectasis
Sever, persistent, unusual or recurrent infections
What investigations can be done to diagnose common variable immunodeficiency?
Reduced immunoglobulins on simple blood test
Decreased IgG always, deceased IgA usually, decreased IgM in ~50%
Normal B lymphocyte count, but immature types
What are treatment options for common variable immunodeficiency?
Early diagnosis and treatment of any infections
Prophylactic immunoglobulin transfusions (IV every 3-4 weeks or SC every week) immunoglobulin reactions can occur (serum sickness)
What is serum sickness?
Flu-like symptoms (but no respiratory component)
Possible thrombotic events or anaphylaxis
Reaction to immunoglobulin treatment
What can be causes of Hyposplenism or asplensim?
Congenital
Post-surgical (after trauma)
Atrophy (after infarcts from thrombosis or sickle cell disease)
Functional (malignancy, coeliac disease or IBD)
What is the risk with hypo/asplensim? Which groups of people are at particular risk?
Increased risk of severe infection with encapsulated bacteria Strep. pneumoniae, H. influenza, N. meningitides)
Higher risk of malaria and babesiosis
Age 50, poor response to vaccination, previous invasive pneumococcal infection, haematological malignancy, other immunosuppression
What are clinical features of Hyposplenism?
Respiratory tract infection possibly with sepsis
What investigations can be done to diagnose Hyposplenism?
Spleen function assessed by imaging (USS)
Blood films show Howell-Jolly bodies in erythrocytes (Nuclear DNA Remnants)
What are treatment options for Hyposplenism?
Prevention with vaccination & antibiotics
UK Green Book (Immunisation against Infectious disease)
Pneumococcal, Hib, meningococcal and flu vaccines (with measurement of serological response)
Phenoxymethlypenicillin (oral) if high-risk
Strict malaria prophylaxis and bite avoidance measures
Patient education on early treatment of infections
What is HIV?
Aquired through sex, blood transfusions, iatrogenic
Infects Th lymphocytes (CD4 cells)
CD4
What are clinical features of HIV/AIDS?
Non-specific seroconversion illness after 2-4 weeks Latency for ~10 years before AIDS develops Cerebral toxoplasmosis PML (progressive multi focal leukoencephalopathy) due to JC virus HSV ulcers (chronic) Pneumocystis pneumonia (recurrent) Tuberculosis Intestinal cryptosporidiosis Cryptococcal meningitis CMV retinitis Oesophageal candidiasis Pneumococcal pneumonia Atypical mycobacterial infection Intestinal isosporiasis
What investigations can be done to diagnose HIV?
Low lymphocytes / high immunoglobulins
HIV tests (serology & antigen-detection)
CD4 count / HIV viral load
What are treatment options for HIV?
Initially targeted at opportunistic infections
Prophylaxis against infections where possible (eg. toxoplasmosis, cryptococcosis, pneumocystis pneumonia, mycobacterium avium complex)
Anti-retroviral combination drugs, typically 3-4 given for life
What is the prognosis of HIV and AIDS?
AIDS without treatment: death in 1-3 years
HIV with treatment: almost normal life expectancy
What are clinical features of Immunosuppression caused by steroids and other drugs?
All cause risk of new infections
Steroids: risk of CMV reactivation
Methotrexate, azathioprine, cyclosporine: increase risk of lymphoma
Anti-TNF drugs: re-activation of TB
What is neutropenic sepsis?
Development of fever, often with other signs of infection in a patient with an abnormally low neutrophil count
Absolute neutrophil count
What molecules are involved in neutrophil recruitment to a site of injury?
Selectins on neutrophils and endothelium allow rolling
At sites of injury, integrins are expressed and cause adhesion of the neutrophils
What organisms can cause neutropenic sepsis?
Bacteria: Staph aureus, E. Coli, Pseudomonas aeruginosa
Fungi: after prolonged neutropenia, Difficult to diagnose, Antifungals added if fever does not respond to antibiotics
What is the empirical treatment for neutropenic sepsis?
Tazobactam-piperacillin (Tazocin)
Vancomycin (If no response at 48 hours and lines in)
Antifungal: Voriconazole/Amphotericin B (If no response at 72 hours)
20 year old, lots of chest infections as a child, was tested for cystic fibrosis – neg, Bad acne as a teenager, Recurrent skin abscess. Chronic cough, Persistent lymphadenitis. Burkholderia cepacia infection isolated. DHR not oxidised by neutrophils, so no shift in DHR fluorescence. What is the likely diagnosis?
Chronic granulomatous disease
What can be common causative organisms and clinical manifestations in chronic granulomatous disease?
Recurrent bacterial infections: Pneumonia, Abscesses, Lymphadentiis, Osteomyelitis, Bacteraemia
Predominant organisms: Staphylococcus aureus, Burkholdia (Pseudomonas) cepacia, Serratia marcescens
23 yr old woman has everal episodes of pneumococcal pneumonia and sinusitis. She has seronegative polyarthritis, chronic intermittent diarrhoea but colonoscopy normal. Low levels of IgG and IgA, what is the likely diagnosis?
Common variable immunodeficiency
What are clinical manifestations of common variable immunodeficiency?
Infections Hematologic or organ-specific autoimmunity Chronic lung disease Bronchiectasis Gastrointestinal inflammatory disease Malabsorption Granulomatous disease Liver disease/hepatitis Non Hodskins Lymphoma Other cancers
What infections may be common in someone with common variable immunodeficiency?
Sino-pulmonary: Bacterial (pneumococcal, haemophilus)
Chronic giardia
Infective complications of chronic lung diseases: Bronchiectasis, obstructive airways disease
35 year old woman, Cough and shortness of breath, No response to course of amoxicillin, seen by dermatology for dermatitis, Referred to haem because of persistent lymph nodes
O2 sats – 94% fall to 82% on climbing stairs, WCC normal, CRP 65, CD4 count 12, Sputum – Pneumocystis jirovecii PCR pos. What is the diagnosis?
HIV
What investigations should be used to identify common immunodeficiencies?
Full blood count
Immunoglobulins
Serum complement
HIV testing
What phases do T cells go through from being immature to maintenance?
Initiation: APC presents antigen to T cell
Clonal expansion
Contraction
Maintenance
By what mechanism do B cells adapt to recognise new antigens?
Somatic hypermutation
Programmed process of mutation affecting variable regions of immunoglobulin genes but only affects individual immune cells
What are immature B cells called?
Centroblasts
Which become centrocytes
Which become plasma cells or memory B cells
Where are the antigens which b and T cells target?
B cells: extracellular
T cells: intracellular
What types of immunosuppressive drugs are there?
Corticosteroids
Cytotoxic drugs
T cell suppressant
Antibody/biologics
What is membranous glomerulonephritis?
Commonest in adult
Autoantibodies against the phospholipase A2 receptor 1 in the basement membrane
Immune complex formation in the glomerulus
Triggers membrane attack complex on glomerular epithelium causing it to become leaky
What is minimal change disease?
Commonest in children T / B cell dysfunction Glomerular permeability factor Proteinuria and oedema Lacks evidence of pathology on light microscopy
What is the first line treatment for minimal change disease? And how does it work?
Prednisolone: inhibitors transcription factors so reduced cytokine production, therefore reduced clonal expansion of t helper cells
Ubiquitous expression of corticosteroid receptor
Interrupts multiple steps in immune activation
Inhibit antigen presentation (Innate)
Inhibit cytokine production and proliferation of lymphocytes (Adaptive)
What are some autoimmune indications for plasma exchange?
Severe vasculitis
Good pasture’s disease: antibodies attack basement membrane in lungs and kidneys
Gillian Barre syndrome: antibodies against myelin/nerve axons in PNS
Myasthenia gravis: antibodies against ACh receptor
Antibody mediated transplant rejection
What are Sirolimus and Everolimus? And what is their mechanism of action?
mTOR inhibitors
Block cell cycle progression in G1
Blocks IL2 mediated activation of T & B cells
Reduced clonal proliferation of T cells
What are side effects of mTOR inhibitors?
Hypertriglyceridaemia
Hypercholesterolaemia
Pneumonitis
Oral ulcers
What are advantages of mTOR inhibitors?
Reduce cancer risk
Not nephrotoxic
What is Rituximab and what is its mechanism of action?
Monoclonal antibody against surface determinant on B-cells (CD20)
B cell depletion
What are side effects of Rituximab?
Neutropenia
Hypogammaglobulinemia
Reactivation of latent infections
What is alemtuzumab?
Monoclonal antibody to cell determinant CD52
T cell depletion
What are side effects of alemtuzumab?
Leukopenia
Infection
What is infliximab? What is its mechanism of action?
Antibody against TNF-alpha
Reduction of pro-inflammatory cytokines, leukocyte migration and activation
Subsidence of inflammation
What are side effects of infliximab?
Infusion reactions Neutropenia Infections (TB) Demyelinating disease Heart failure Cutaneous reactions Malignancy Induction of autoimmunity
In what conditions might you use infliximab as treatment?
RA, IBD, Psoriasis and Ankylosing spondylitis
What is Behçet’s disease?
Immune mediated small vessel systemic vasculitis
Mucous membrane ulceration and ocular problems
Recurrent oral aphthous ulcers, genital ulcers, uveitis
What is an antigen?
Substance capable of generating an immune response
What is immunological tolerance?
Unresponsiveness of immune system to an antigen, induced by previous exposure to that antigen
What is autoimmunity?
Immune response to self-antigens due to a failure of immunological tolerance
When specific lymphocytes encounter antigen for the first time they may be…?
Activated leading to an immune response
Inactivated or destroyed leading to tolerance
What is a tolerogen?
Antigen which induces tolerance
What is an immunogen?
Antigen which induces an immune response
What role does infection play in loss of immune tolerance?
Allows bystander activation of auto-reactive cells
Molecular mimicry
What fates do lymphocytes have which would react to self antigens in a healthy person?
Deleted
Inactivated
Undergo a change in their specificity
Where can self tolerance be induced?
Central: B cells in bone marrow, T cells in thymus
Peripheral
Describe central immunological tolerance to self antigens
Induced in immature lymphocytes in generative lymphoid organs. B cells in bone marrow, T cells in Thymus
If cells react to self antigens: Apoptosis: Cell deletion
Change in receptor until no longer self reactive (B Cells)
Develop into regulatory T cells (CD4+ Cells), Mature and enter peripheral circulation, where peripheral tolerance will cause cell to undergo: anergy, deletion or suppression
Antigens that lymphocytes encounter in generative organs are…?
Self antigens
External antigens are not usually found in generative lymphoid organs but remain in peripheral lymphoid tissue
Describe peripheral immunological tolerance to self antigens
Mature lymphocytes
Deletion: Induction of apoptosis in self-reactive lymphocytes
Anergy: Render self-reactive lymphocytes incapable of reacting antigen upon re-exposure
Suppression: T Regulatory Cells suppress self-antigen specific lymphocytes
Describe clonal deletion
CD4+ T cells which show high avidity self-reactivity are
negatively selected in the thymus
What are the determinants of negative selection in clonal deletion?
Presence or absence of self-antigen in thymus, determined by autoimmune regulator (AIRE) protein (transcription factor) whichcontrols expression of thymic epithelial cells which express tissue restricted antigens (major proteins from elsewhere in body)
Affinity of T-Cell Receptor (TCR) for antigen. High affinity = increased chance deletion
What is anergy as a mechanism of peripheral tolerance?
Exposure of CD4+ T cells to antigen in absence of co- stimulation or innate immunity leads to CD4+ T cells becoming incapable of reacting to that antigen
What 2 signals are required for T cell activation? What happens if these are not present?
T cell receptor binding Ag presented on MHC
Recognition of co-stimulators by CD28
If this is absent, prolonged stimulation by antigen will lead to anergy
Co-stimulators are only expressed on antigen presenting cells when then are activated e.g. by innate immunity or inflammation
What are the 2 main inhibiting receptors which regulate T cell responses?
CTLA-4: Member of CD28 family, expression up-regulated in T cells exposed to antigen and terminates continued activation of these cells. Expressed on regulatory cells and mediates suppressive function. Acts to block T cell receptor signalling and reduce availability of co-stimulatory molecules on APC
PD-1: Binds to ligand on APC and inactivates the T Cells
Where is CTLA 4 important in inhibiting T cells?
Centrally
Where is PD-1 important in inhibiting T cells?
Peripherally
What does suppression by regulatory T cells lead to inhibition of?
Effector T Cell production
B Cell production
NK Cell production
What does generation of regulatory T cells require?
Cytokines, especially Il-2 (promotes differentiation into T-regs)
What do regulatory T cells do?
Produce immunosuppressive cytokines
Reduce ability of APCs to stimulate T Cells
Consumption of Il-2 (necessary growth factor for other cell populations)
What are important factors in CD8+ T cell tolerance?
Co-stimulation presence or absence
Inhibitory receptors: PD-1
T-Reg cells can control activation
By what processes does central B cell tolerance occur?
Deletion
Receptor editing: non-self antigen specificity is reached
Anergy: Occurs if cells recognise self-antigen weakly
By what processes does peripheral B cell tolerance occur?
In the absence of T Helper Cells
Apoptosis
Anergy (via engagement of inhibitory receptors)
What type of course do autoimmune diseases often follow?
Chronic, progressive, relapsing and remitting
What immune abnormalities can lead to autoimmunity?
Defective tolerance or regulation
Abnormal display of self antigens
Inflammation or an initial immune response
What abnormalities can occur, leading to defective tolerance or regulation?
Imbalance between lymphocyte activation and control due to: Defects in negative selection Defects in reg T cells Defects in apoptosis Inadequate function of inhibitory cells
What abnormalities might occur which result in an abnormal display of self antigens?
Increased expression
Structural changes
Exposure of hidden antigens
How can inflammation lead to autoimmunity?
Activate APC, therefore enabling co-stimulation and activation not anergy of self recognising lymphocytes
Describe autoimmunity as a polygenic multifactorial disease
Inheritance of multiple genetic polymorphisms contributing to susceptibility: Some disease specific, Some generic for autoimmune disease
Contribution of variable environmental factors
Which autoimmune conditions are associated with HLA-B27?
Ankylosing spondylitis, reactive arthritis
Which autoimmune condition is associated with HLA-DR2?
Systemic lupus erythematosus (SLE)
Which autoimmune conditions are associated with HLA-DR3?
Atoimmune hepatitis, Sjögren’s syndrome, T1DM, SLE
Which autoimmune conditions are associated with HLA-DR4?
Rheumatoid arthritis, T1DM
What infections can trigger autoimmune conditions?
Streptococcal infection → rheumatic fever
urethritis or gastroenteritis → reactive arthritis
Campylobacter gastroenteritis → Guillain–Barré syndrome
How can infection lead to autoimmune conditions?
Molecular mimicry
What chemicals can lead to autoimmune disorders?
Anti-convulsants or antibiotics →drug-induced lupus
Halothane (general anaesthetic) →liver necrosis
What autoimmune condition can result from a teratoma?
Autoimmune encephalitis
Exposure of self antigens in which protected sites could lead to autoimmune destruction?
Eye
Testes
What is the significance of autoimmune conditions being mainly B cell mediated?
Easier to diagnose (eg. antibody detection tests)
Can occur in utero (eg. neonatal thyrotoxicosis, neonatal lupus)
What types of hypersensitivity reactions can cause autoimmune conditions?
Type 2: Antibody mediated e.g. Graves
Type 3: Immune-complex mediated e.g. SLE
Type 4: T-cell mediated
How can antibodies lead to autoimmune conditions?
Antibodies bind to antigens on cells: cause recruitment of inflammatory cells and tissue injury
Can cause abnormal cellular function e.g. Graves’
Antigen-antibody complexes forming in circulation: induce vascular inflammation with ischaemia to associated tissue
How can immune complexes lead to autoimmune conditions?
Ag (self or foreign) and Ab complex deposit in tissues and induces inflammation
Amount of complex deposited in a tissue is determined by nature of the complex and characteristic of the blood vessels
How can T cell mediated autoimmunity lead to disease?
Trigger inflammation leading to tissue injury
How can cytokines lead to autoimmune disease?
Immune-mediated inflammation (TH 1 and 17) via secretion of cytokines that recruit and activate leukocytes
Delayed hypersensitivity: Activation of CD4+ T cells with inflammation 24-48 hrs after challenge
What would you measure levels of to confirm Graves’ disease?
TSH receptor
What would you measure levels of to confirm Hashimoto’s thyroiditis?
Thyroid peroxidase
What would you measure levels of to confirm Rheumatoid arthritis?
Rheumatoid factor
What would you measure levels of to confirm SLE?
ANA and dsDNA
What would you measure levels of to confirm Sjögren’s syndrome?
ANA
What would you measure levels of to confirm Coeliac disease?
Anti-gliadin and anti-endomysial
What would you measure levels of to confirm Primary biliary cirrhosis?
ANA and AMA (anti mitochondrial antibodies)
What would you measure levels of to confirm chronic autoimmune hepatitis?
SMA (smooth muscle antibodies) and LKM-1 (liver kidney microsomal type 1)
What would you measure levels of to confirm Wegeners granulomatosis?
c-ANCA (anti neutrophil cytoplasmic antibody)
What is Wegeners granulomatosis?
Form of vasculitis that affects small vessels in organs
Lung and kidney damage
What are the most prevalent autoimmune conditions?
Graves’ disease
Rheumatoid arthritis
What may be clinical features of anti phospholipid syndrome?
thrombophilia
recurrent miscarriages
List some symptoms of systemic lupus erythematosus
Systemic : malaise, fever, weight loss
Skin : rash, photosensitivity, vasculitis, hair loss
CNS : cerebral lupus, transverse myelitis
Heart : pericarditis, Libman-Sacks endocarditis
Lungs : pleural effusions, pulmonary fibrosis
Kidneys : glomerulonephritis
Blood : anaemia, leukopenia, thrombocytopenia, 2° anti phospholipid syndrome
Other : 2° Sjögren’s syndrome, arthralgia, non-deforming arthritis
Describe the pathogenesis of SLE
Susceptibility genes: b and T cells specific to self nuclear antigens
External triggers: defective clearance of apoptotic bodies so increased burden of nuclear antigens
Anti nuclear antibodies: form complexes which are endocytosed and stimulate B cells, resulting in high levels of anti nuclear IgG production
What investigations results would you expect in SLE?
FBC =↓Hb (chronic/haemolytic),↓WCC,↓Plts
ESR : raised
CRP : moderately raised
ANA : 95% sensitivity
dsDNA : 50% sensitivity & 99% specificity
anti-cardiolipin (phospholipid) antibodies
What treatment is given for SLE?
Sun-avoidance / sun screens
Steroids : as for other autoimmune rheumatological disorders
NSAIDs : as for other autoimmune rheumatological disorders
DMDs : hydroxychloroquine, azathioprine (anti-proliferative), cyclophosphamide (anti-proliferative)
mAbs : rituximab (anti-CD20 on B lymphocytes)
