Core clinical immunology Flashcards
What is allergy and hypersensitivity
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system directed against innocuous antigens in a pre-sensitized host
What is the immune response to parasitic disease
Increased levels of IgE Tissue inflammation with: -Eosinophil and mastocytosis -Basophil infiltration Presence of CD4+ T cells secreting: -IL4, IL5 and IL13
What is the role of Th2 T cell
Multiple cytokine release
Innate inflammatory response
Drive for immunoglobulin production
What is rhinitis
Blocked/ runny/ itchy nose, sneezing often with eye symptoms (itching/burning/watery eyes, redness)
What are the two types of rhinitis and they’re causes
Allergic:
- Seasonal (Pollen, moulds)
- Perenial (House dust mite, animal dander)
Non-allergic (vasomotor, infective, structural, drugs, hormonal, polyps)
What is asthma
Disease of inflammation and hyper-reactivity of small airways
Immediate symptoms are IgE mediated
Damage to airways due to late phase response
Damaged airways are hyper reactive to non-allercic stimuli
What are the classifications of dermatitis
Eczema -Atopic -Non-atopic Contact dermatitis -Allergic -Non-allergic Other types (discoid eczema, photosensitive dermatitis, seborrhoea dermatitis)
How are allergies diagnosed
History Specific IgE Skin prick test (>2mm wheal) Intra-dermal test Graded challenge test Basophil activation test Component resolved diagnostic
What is a skin prick test
Prick skin and measure wheal formed
Positive if more than >2mm wheal
What is an intra dermal test
Inject into dermal layer of skin and look for increase in size of lump
Positive if increase by more the 3mm
What are the treatments for allergies
Antihistamines Steroids Adrenaline Avoidance Immunotherapy
What is the mechanism of immunotherapy
Diverts immune response from Th2 to Th1 pathways
What are major food allergens
Cow's milk Egg Legumes (peanuts, soybean, tree nuts) Fish Crustaceans/molluscs Cereal grains
What are the clinical manifestations of adverse reactions to food
Gastrointestinal: -vomiting -diarrhoea -oral symptoms Respiratory (upper and lower) -rhinitis -bronchospasm Cutaneous -urticaria -angioedema -role of food in atopic dermatitis is unclear Anaphylaxis
What is important in history of drug allergy
Indication for the drug
Detailed description of the reaction
Time between drug intake and onset of symptoms
Number of doses taken before onset
Aware of pharmacological effects and non-immunological ADR
What is the management of drug allergy
Intradermal testing
Graded challenge
Desensitization
What cells are involved in the innate immune system
Macrophages Dendritic cells Mast cells Neutrophils Complement
What cells are involved in the adaptive immune system
T cells
B cells
What are the features of the innate immune system
Pattern recognition against broad classes of antigen No memory No amplification Little regulation Fast response Short duration
What are the features of the adaptive immune system
Highly specific (T and B cell receptors) Strong memory and amplification component Many regulatory mechanisms Slow response Responses may last months- years
How do the immune systems interact
- Innate cells directly detect and attack antigenic targets:
- occurs at sites of infection
- phagocytosis
- -cytotoxicity
- -inflammatory mediators and chemokine to attract other cells
-Dendritic cells present antigen to T cells
- Cross talk between Dendritic cells, T cells and B cells:
- Immune memory to determine specific learned responses
- -Occurs in lymphoid tissues
- Adaptive immune cells activate innate immune cells directing tissue inflammation to specific targets
- T cell cytokines activate monocytes, macrophages
- -B cell antibodies activate complement
What are the phagocytic cells of the innate immune system and what do they do
Neutrophils: eat and destroy pathogens
Macrophages: eat and destroy pathogens and produce chemokine to attract other immune cells
Dendritic cells: Eat and destroy pathogens and present antigen to adaptive immune system
What is the role of cytokines
Signal between different immune cells (innate to adaptive, adaptive to innate)
What are the roles of the complement components of the innate immune system
Directly attacks pathogens via alternative and lectin pathways
May be activated by adaptive immune system via antibodies
What are the roles of the histamine-producing cells
Vasodilation Attract other immune cells Defence against parasites Wound healing Allergy and anaphylaxis
What do mast cells, basophils, eosinophils do
Produce histamine and other chemokine and cytokines
What do T cells do
Cause inflammation by inflammatory cytokines or by helping B cells make autoantibodies
What is the defining characteristic of autoimmunity
The adaptive immune system recognises and targets the body’s own molecules, cells and tissues
What are the characteristics of autoimmunity
T cells that recognise self antigens
B cells and plasma cells that make autoantibodies
Inflammation in target cells, tissues and organs is secondary to actions of T cells, B cells and antibodies
What are the characteristics of autoinflammation
Seemingly spontaneous attacks of systemic inflammation
No demonstrable source of infection as precipitating cause
Absence of high-titre autoantibodies and antigen specific autoreactive T cells
No evidence of auto-antigenic exposure
What is autoimmunity
Theoretical concept
Breakdown of self-tolerance
Many cells of the immune system have capacity for autoimmune functions
Overlap with normal immune functions such as anti-tumour immunity
Some people have autoantibodies without any symptoms
What is autoimmune disease
Distinct clinical entities
Environmental factors acting on favourable genetic background
Wide variety of pathogenic mechanisms between diseases
Autoimmunity leading to inflammation, organ dysfunction and damage
Where are T cells and B cells selected
T: thymus
B: bone marrow
What are some antigenic factors of autoimmunity
Infections that trigger autoimmune responses
Environmental triggers: UV light, smoking
Alterations in self-proteins that increase their immunogenicity
What are organ specific diseases
Affect a single organ
Autoimmunity restricted to autoantigens of that organ
Overlap with other organ specific diseases
Autoimmune thyroid disease is typical
What are systemic diseases
Affect several organs simultaneously
Autoimmunity associated with auto antigens found in most cells of the body
Overlap with other non-organ specific diseases
Connective tissue diseases are typical
What is Hashimoto’s thyroiditis
Destruction of thyroid by autoimmune process
Associated with autoantibodies to thyroglobulin and to thyroid peroxidase
Leads to hypothyroidism
What is Grave’s disease
Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
Leads to hyperthyroidism
What are some connective tissue diseases
Systemic lupus erythematosus Scleroderma Polymyositis Sjogrens syndrome Ubiquitous antigens (components of cell nucleus) cause multi system inflammation
How is autoimmune disease spotted
Clinical history taken
Examination of patient
Perform blood testing
What is the meaning of sensitivity
Measure of how good the test is in identifying people with the disease
What is the meaning of specificity
Measure of how good the test is at correctly defining people without the disease
What are the types of diagnostic tests
Non specific: inflammatory markers
Disease specific: autoantibody testing, HLA typing
What are the non-specific markers of systemic inflammation
ESR CRP Ferritin Fibrinogen Haptoglobin Albumin Complement
What are antinuclear antibodies (ANA)
Antibodies in the patient’s blood that bind to the cell nucleus
What is the function of the immune system
Protect the body from infection:
- recognise pathogens
- mount an immune response which requires cell-cell communication
- Clear the pathogen which may require adaptive responses to changing pathogen
- self-regulation which is important to minimise host damage
What is immunodeficiency
Clinical situations where the immune system is not effective enough to protect the body against infection
What is primary immunodeficiency
Inherent defect within the immune system - usually genetic
What is secondary immunodeficiency
Immune system affected due to external causes
What are secondary causes of immunodeficiency
- Breakdown in physical barriers: cystic fibrosis
- Protein loss: burns, protein loosing enteropathy, malnutrition
- Malignancy: especially lymphoproliferative disease, myeloma
- Drugs: Steroids, DMARDS, Rituximab, anti-convultants, myelosuppressive (chemotherapy)
- Infection: HIV, TB
What are pathogen recognition receptors
Recognise pathogen associated molecular patterns which are unique to each pathogen
Phagocytes use PRRs to detect pathogens
What is an example of a pathogen associated molecular pattern
Lipopolysaccharide
What is a Toll like receptor
type of pathogen recognition receptor
TLR4 recognises lipopolysaccharide
TLR5 recognises flagellin
What is the result of lack of TLR3
Unable to recognise virus and can lead to recurrent HSV encephalitis
What is CRP
A marker of inflammation
How does IRAK4 and MyD88 deficiencies present
Recurrent bacterial infection especially streptococcus and staphylococcus - pneumonia, meningitis, arthritis
Poor inflammatory response
Susceptibility to infection decreases with age
How do you treat IRAK4 and MyD88 deficiencies
Prophylactic antibiotics, IV immunoglobulin if severe
How does chronic granulomatous disease present
Recurrent abscesses: lung, liver, bone skin, gut
Infection by: Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi
It is X -linked so commonly presents in males
How is chronic granulomatous disease tested
Function of macrophages
Rely on reduction (gain of electron)
Measure dihydrohodamine reduction using flow cytometry, on blood chart the curve should shift over time when the macrophages are working but it will stay the same if they have the disease.
Nitro blue tetrazolium dye reduction where healthy neutrophils should go purple
What is immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve a desired immune response
What will the therapeutic effect of immunomodulation
May lead to immunopotentiation, immunosuppression, or induction of immunological tolerance
What are immunomodulators
Medicinal products produced using molecular biology techniques including recombinant DNA technology
What are the classes of immunomodulators
Substances that are nearly identical to the body’s own key signalling proteins
Monoclonal antibodies
Fusion proteins
What is immunopotentiation
Enhancement of the immune response by increasing the speed and extent of its development and by prolonging its duration
What is passive immunisation
Transfer of specific, high titre antibody from donor to recipient
Provides immediate but transient protection
What are the problems of passive immunisation
Risk of transmission of viruses
Serum sickness
What are the types of passive immunisation
Pooled specific human immunoglobulin Animal sera (antitoxins and antivenins)
What are the uses of passive immunisation
Hep B prophylaxis and treatment Botulism VZV (pregnancy) Diptheria Snake bites
What is active immunisation
To stimulate the development of a protective immune response and immunological memory
What are the problems with active immunisation
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
What are agents of immunosuppression
Corticosteroids Cytotoxic agents Anti-proliferative/ activation agents DMARDs Biological DMARDs
What are the actions of corticosteroids
Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
Lymphopenia
Decreased T cells proliferation
Reduced immunoglobulins production
What are the side effects of corticosteroids
Carbohydrate and lipid metabolism leading to diabetes and hyperlipidaemia
Reduced protein synthesis leading to poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
What are the uses of corticosteroids
Autoimmune diseases (CTD, vasculitis, RA)
Inflammatory diseases (Crohn’s, sarcoid, GCA/polymyalgia rheumatica)
Malignancies (lymphoma)
Allograft rejection
What drugs target lymphocytes
Antimetabolites:
- Azathioprine (AZA)
- Mycophenolate mofetil (MMF)
Calcineurin inhibitors:
- Ciclosporin A (CyA)
- Tacrolimus (FK506)
M-TOR inhibitors:
- Sirolimus
IL-2 receptor mABs:
- Basiliximab
- Daclizumab
What are the actions of Calcineurin inhibitors
CyA binds to intracellular protein cyclophilin
Tacromilus binds to intracellular protein FKBP-12
Prevents activation of NFAT
Factors which stimulate cytokines gene transcription
Reversible inhibition of T-cell activation, proliferation and clonal expansion
What are the actions of sirolimus (rapamycin)
Macrolide antibiotic that binds to FKBP12 and insist mammalian target of rapamycin
Inhibits response to IL-2
Cell cycle arrests at G1-S phase
What are the side effects of Calcineurin/ mTOR inhibitors
Hypertension Hirsutism Nephrotoxicity Hepatotoxicity Lymphomas Opportunistic infections Neurotoxicity Multiple drug interactions
What do antimetabolites do
Inhibit nucleotide synthesis
Azathioprine:
- guanine anti-metabolite
- rapidly converted into 6-mercaptopurine
Mycophenolate mofetil (MMF) -prevents production of guanosine triphosphate
Impaired DNA production
Prevents early stages of activated T and B cells proliferation
What are the side effects of cytotoxic drugs
Bone marrow suppression Gastric upset Hepatitis Susceptibility to infections Cystitis Pneumonitis
What are the clinical uses of cytotoxic drugs
AZA/MMF:
- Autoimmune diseases (SLE, vasculitis, IBD)
- Allograft rejection
MTX:
- RA, PSA, Polymyositis, vasculitis
- GvHD in BMT
Cyclophosphamide:
- Vasculitis (Wagner’s, CSS)
- SLE
What are examples of biologics
Anti-cytokines (TNF, IL-6 and IL-1) Anti-B cell therapies Anti-T cell activation Anti-adhesion molecules Complement inhibitors Check point inhibitors
What are types of adoptive immunotherapy
Bone marrow transplant
Stem cell transplant
What are the uses of adoptive immunotherapy
Immunodeficiencies
Lymphomas and leukaemia
Inherited metabolic disorders (osteoporosis)
Autoimmune diseases
What are the immunomodulators used in allergies
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
What are the indications for allergen specific immunotherapy
Allergic rhinoconjunctivitis not controlled on maximum medical therapy
Anaphylaxis to insect venoms
What are the mechanisms of allergen specific immunotherapy
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T regulatory cells and tolerance
Routes:
SC or sublingual for aero-allergens
What are the side effects of allergen specific immunotherapy
Localised and systemic allergic reactions
What are the innate defences
Skin (barrier, sebum, normal flora)
Mucous membranes (tears, urine flow, phagocytes)
Lungs (goblet cells, muco-ciliary escalator)
Interferons, complement, lysozyme, acute phase proteins
Normal commensal flora in gut
What are qualitative and quantitative defects of neutrophils
Qualitative (lose ability to kill or chemotaxis)
Quantitative (less present)
What is a neutropenic patient
When a patient has reduced neutrophils <0.5x10^9/L
How are hypogammaglobulinaemias treated and what are they
Antibody problems
Treated using immunoglobulin
What is the role of the spleen
Source of complement and antibody producing B cells, removes opsonised bacteria from blood
How are infections investigated
History and exam Urgent diagnosis and treatment Blood cultures Respiratory samples Other samples as systems suggest eg urine, serology samples - antibody/antigen Radiology Histopathology
What are the general principles of prevention when managing infection in immunocompromised patients
Hand washing, aseptic technique, protective isolation, HEPA air filtration
Vaccines (avoid live in T cell deficient)
Prophylactic antimicrobials and passive immunoglobulin
Special diet
What is SIRS and how will it present
Systemic inflammatory response syndrome Temp >38 Heart rate >90 Resp rate >20 WBC >12
What is sepsis
SIRS and suspected focus of infection
What is septic shock
Sepsis and low blood pressure (<90/60)
What is the bufalo management
Blood cultures (2 sets) Urine output (catheterise) Fluid (500ml IV saline/15mn) Antibiotics Lactate (arterial blood gas) Oxygen (15 l/min via reservoir face mask)
What is cellulitis
Skin and soft tissue infection
Caused by gram positive cocci (staph aureus and strep pyogenes)
Treated with flucloxacillin
What is necrotising fasciitis
A sever skin and soft tissue infection caused by a polymicrobial mix but usually involving streptococcus pyogenes
How is necrotising fasciitis treated
Debridement
Meropenem
Clindamycin
What is infective endocarditis
Infection od heart valves Many possible bugs Most common: -staph aureus -streptococci
How is infective endocarditis treated
6 weeks IV antibiotics depending on bug
Why are people predisposed to brain abscess
Immunosuppression
HIV
Intravenous drug use
Endocarditis
What is the treatment for a brain abscess
Drainage
ABx for 4+weeks based on bug
What are the antibiotic rules during pregnancy
Beta lactams are the most well tolerated antibiotics and safe in pregnancy (penicillins, cephalosporins, meropenem)
Avoid in pregnancy:
-Quinolones (damage to cartilage)
-Trimethoprim (folic acid antagonist)
-Tetracyclins (deposits and stains bones/teeth)
What is the difference between HLA and MHC molecules
HLA (human leukocyte antigens) are only found in humans whereas MHC (major histocompatibility complex) molecules are commonly found in many vertebrates
What is HLA
A gene complex present in human chromosome 6 which encodes for both classes of MHC molecules
What is the likelihood that siblings will have the same HLA molecules and why is that important
1 in 4 so an enormous registry is required for transplant which need an exact match (eg bone marrow)
What are the characteristics of the two HLA classes
Class 1:
- A, B, C
- all cells except RBCs as no nucleus
- Heavy chain and B2m
Class 2:
- DR, DQ, DP
- antigen presenting cells
- heterodimer
What are class 1 MHC molecules good at handling
Intracellular peptides
What are class 2 MHC molecules good at handling
Foreign molecules that are endocytosed
What is the purpose of MHC molecules
Part of defence against infection
What starts the process of rejection of a transplant and what modulate the action
APCs of foreign cells of transplant migrate to the lymph nodes and thus start process of rejection
Complement, PRRs, innate immune cells all modulate rejection
CD4 T cells set up delayed hypersensitivity reactions
What is an autologous cell
Manufactured as a single lot from the patient being treated
What is an allogenic cell
Manufactured in large batches from unrelated donor tissues
What is the purpose of HLA typing
A way to predict transplant rejection and minimise the chance of this occurring
How are successful transplants achieved
Ensuring transplant material is as well matched as possible
T cells are suppressed using drug therapy to prevent a strong immune reaction
What are the two types of HLA typing
Serological - cell based Molecular: - Extraction of DNA - Amplification - Detection of sequence polymorphisms (ie tissue types) -- hybridisation to probes -- sequencing
What are the benefits of HLA testing
Less rejection episodes
Better graft survival
National kidney waiting lists so can work out the best match from register
Less sensitisation
Establish relationships (eg paternity testing)
What happens in antibody detection
Screen regularly for antibodies to prevent hyper acute rejection pre- and post-transplant
What is the complement dependent cytotoxicity test
CDC
Detects complement fixing IgG/ IgM HLA anf non-HLA using blood and serum
What are the advantages of CDC
> 30 years experience
Inexpensive
What are the disadvantages of CDC
Limited sensitivity Subjective Non-complement fixing antibodies Viable reagent supply and quality control Non-HLA antibody interference
What is Flow cytometry
Laser shines into cells
Fluorescent dyes are used and if antibodies are present then there is a shift in fluorescence
What is lumina screening
Similar to flow cytometry but uses beads
Very sensitive
What are the types of rejection
Acute antibody mediated rejection
Acute cellular rejection
Chronic antibody mediated rejection
Hyperacute rejection
What is a hyper acute rejection
As soon as blood flows into transplanted organ, rejection process happens
What is acute cellular rejection
T cell dependent
-use T cell immunosuppression
Directed against HLA molecules as the effect of HLA mismatch
Happens 7-10 days after transplant
How are hyper acute rejection minimised
Blood group matched
HLA matched
Gal antibodies to lower species
What is the function of complement
Should lyse foreign cells if the foreign cells are covered in antibody and will trigger the classical complement cascade
How does complement deficiency present
C2, C4 deficiency:
- SLE
- Infections
- Myositis
C5-C9 (which form membrane attack complex) deficiency:
-Presents with repeated episodes of bacterial meningitis (particularly Neisseria meningitis)
What are some B cell defects
CVID
IgA deficiency
X linked hyper IgM syndrome
Transient hypogammaglobuliaemia of infancy
Secondary antibody deficiency due to drugs
What are the results of B cell defects
Loss of antibody secretion
Usually leads to recurrent bacterial infection with pyogenic organisms
Treat with antibiotics then IV IgG for life
Most are very serious (except IgA deficiency)
What is the treatment for antibody deficiency
Antibiotics
Immunoglobulin G replacement
What are the results of T cell defects
More severe since B cells also need T cell help so even if there are B cells they won’t function
Symptoms are recurrent infection with opportunistic infections, bacteria, viruses, fungi (candida), protozoa (pneumocystis)
What are some types of defects in T cells
SCID (severe combined immunodeficiency)
DOCK8 deficiency
What is SCID
Severe combined immunodeficiency No T cells and suggestive history Paediatric emergency Antibiotics, antivirals, antifungals Asepsis Haemopoietic stem cell transplant is the only cure
What are the causes of SCID
Defect/ absence of critical T cell molecule (TCR, common gamma chain)
Loss of communication (MHC2 deficiency)
Metabolic (adenosine deaminase deficiency)
