Immunology, Hypersensitivity, Autoimmunity and Immunosupressants Flashcards
What chemical barrier do cells at the surface e.g. Panneth cells, epithelial cells have which can penetrate bacteria cell walls and lyze them?
Antimicrobial peptides
What does a neutrophil look like under a microscope?
Multi-lobular nucleus and granular cytoplasm
What are the 3 pathways that cause complement activation in the innate immune response?
1st - Alternate pathway (pathogen surface creates environment for complement activation)
2nd - Lectin pathway (mannose-binding lectin binds to pathogen surface)
3rd - Classical pathway (antibody binds to antigen)
What does complement activation in the innate immune response cause?
- Recruitment of inflammatory cells
- Opsonization of pathogens, facilitating uptake and killing by phagocytes
- Peroration of pathogen cell membranes
What do lymphocytes look like?
Small white blood cells with large nuclei
What is the function of these differentiated T cells?
a) TH17
b) Treg
c) TH1
d) TH2
e) TFH
a) Reinforce innate immunity
b) Suppression of immune response
c) Macrophage activation
d) Mast cell/ B cell activation
e) B cell activation in lymph nodes
What is meant by T cells being
a) mutually regulated?
b) having phenotypic plasticity?
a) if you have expansion of one T cell type the others are suppressed
b) effector cells can change their function depending on type of infection
What do NK cells do?
Suppress expansion of the virus but doesn’t clear it, need antigen specific T cells for that
What is affinity maturation of plasma cells?
Mutation at the genetic level to produce antibodies with the highest affinity for antigens i.e. isotype switching from IgM to IgG or IgA
What is the function of memory B cells?
- Long lived (quiescent), high affinity class switched Ig ready for immediate neutralising of infections
- Secondary immune response quicker
- IgG response predominates
- Memory T cells also produced
What does the therapeutic monoclonal antibody Rituximab do?
Anti CD20 - kills tumour cells in lymphoma
What does the therapeutic monoclonal antibody Infliximab do?
Anti TNF - blocks inflammation in rheumatoid arthritis
What does the therapeutic monoclonal antibody Impilimumbab do?
Anti CDLA-4 - blocks immunosuppression in melanoma
What drugs can be used in immunotherapy
- Therapeutic monoclonal antibodies
- Corticosteroids
- Cytotoxics
- T cell immunosuppressants e.g. ciclosporin
What are the
a) Central/primary lymphoid organs?
b) Secondary lymphoid organs?
a) Where lymphocytes are produced i.e. Bone marrow = B cells, Thymus = T cells
b) Where adaptive responses start e.g. adenoids, tonsils, spleen, peyers patch, appendix
What is the role of
a) CD4+ T cells
b) CD8+ T cells
a) Help others by producing activating cytokines - recognise antigen presented by dendritic cells
b) Recognise and kill infected cells
What are the symptoms of immunodeficiency?(SPUR)
Serious infections
Persistence of infections (often medication resistant)
Unusual sites or unusual organisms
Recurrent infections
What are the warning signs for immunodeficiency?
- Antibiotics for 2 months without effect
- Persistent thrush in the mouth or elsewhere on skin
- Failure to thrive in babies
- 2 or more pneumonias, deep-seated infections (e.g. cellulitis) or serious sinus infections in a year
- Recurrent deep skin or organ abscesses (cold with no erythema markers)
In primary immunodeficiency, what are patients at risk of when antibody/B cells are affected?
- Bacterial infections - capsulated organisms e.g. streptococci, meningococci, staphylococci
- Protozoal infections
- Abscesses
- Fungi and viruses uncommon
In primary immunodeficiency, what are patients at risk of when T cells are affected?
- Fungi - pneumonia, meningitis, toxoplasma (eye and brain), candida
- Viral infections e.g. Poliovirus, EBV, Herpes etc
- Bacteria infections uncommon and no abscesses
In primary immunodeficiency, what are patients at risk of when phagocytic cells/ neutrophils are affected?
- Bacterial infection - staphylococci, pseudomonads
- Fungi - aspergillus
- Abscesses - cold with little inflammation
- Viral infection uncommon
In primary immunodeficiency, what are patients at risk of when complement is affected?
- Classical pathway - bacterial infections but viral and fungal rare
- Alternate pathway - Neisseria infection (meningitis)
What is SCID?
Primary immunodeficiency disorder where T cells and B cells absent. Difficult to fight viral fungal and bacterial infections - must be isolated and bone marrow transplant.
What is X-linked agammaglobulaemia?
Primary immunodeficiency disorder where there is low/absent B cells and reduced immunoglobulins. Present in boys, absent tonsils and recurrent bacterial infections.
What is common variable immunodeficiency?
Primary immunodeficiency disorder. Low immunoglobulins and multiple gene defects. Autoimmunity, recurrent bacterial infections, high risk of malignancy.
What is chronic granulomatous disease?
Primary immunodeficiency disorder affecting neutrophil oxidative burst that kills the organisms. Recurrent abscesses deep-seated in liver and soft tissue. Fungal. Gingivitis and tooth loss.
What is chronic mucotaneous candidiasis?
Primary immunodeficiency disorder where there’s an inability to clear candida. Cytokine abnormalities and endocrine abnormalities. Can have oesophageal malignancies.
What is DiGeorge syndrome?
Primary immunodeficiency disorder from gene deletion where thymus doesn’t develop, palate doesn’t form properly (speech difficulties), cardiac abnormalities. Viral, fungal and bacterial infections.
What drugs can cause secondary immunodeficiency?
- Cytotoxics
- Anti-convulsants (B cells can’t produce antibodies so will need immunoglobulin replacement)
- Carbimazole for hyperthyroidism (causes mouth ulcers and sepsis)
- Monoclonal antibodies
- Immunosuppressive drugs e.g. ciclosporin and tacrolimus, methotrexate, cyclophosphamide e.tc.
What are the causes of oral candida?
- Dentures
- Connective tissue syndromes e.g. Sjogren’s syndrome
- Secondary immunodeficiency e.g. HIV, drugs
- Steroid inhalers
- Antibiotic therapy
- Primary immunodeficiency
- Dietary
- Xerostomia
- Endocrine
- Others: alcohol, caffeine, Hep C, smoking
What are the causes of mouth ulcers?
- Cancer
- Infection, viral (HSV) or bacterial
- Trauma
- Medications e.g. methotrexate
- SLE
- Crohns disease
- Nutritional deficiencies
- Aphthous
- Oral dermatoses e.g. lichen planus, pemphigoid etc.
What are the causes of gingivitis and tooth loss?
- Scurvy
- Pregnancy
- Chronic granulomatous disease (primary immunodeficiency)
- Ciclosporin
- Poor oral hygiene
- Anti-convulsants
What is Type 1 hypersensitivity?
IgE antibody mediated degranulation of mast cells and basophils. Releases histamine, heparin, lysosomal enzymes and proteases. Allergic reaction.
What is Type 2 hypersensitivity? Give examples of diseases
Antibody mediated autoimmune: IgM and IgG antibodies against cell surface or ECM antigens e.g. haemolytic anaemia, acute rheumatic fever, PEMPHIGUS VULAGARIS!!
In an allergy what is the preferential switch in cytokine profiles?
Type 1 to Type 2
What are the clinical consequences of Type 1 hypersensitivity?
- Urticaria (hives) and Angioedema (swelling)
- Smooth muscle contraction (airways, bladder, GI)
- Capillary permeability
- Reduced BP
- Hypovolaemic shock
What investigations can be undertaken for Type 1 Hypersensitivity reactions?
- Skin prick test
- Blood tests - measures IgE to the allergen
- Challenge test
If a patient has a latex allergy
a) What are their likely predisposing risk factors?
b) What management should be available?
a) - Atopy (asthma, hay fever, eczema)
- Regular exposure
- Spina bifida
b) - Staff awareness
- First appointment
- No latex gloves or equipment
- Wipe down all surfaces
For a local anaesthetic allergy
a) What are the likely signs/symptoms?
b) What types are more common for causing allergies?
a) Vasovagal, tachycardia or collapse
b) Esters (procaine, benzocaine) more common than amides (lidocaine, articaine, prilocaine, bupivacaine)
What antibiotic is most common for causing allergies?
Penicillin
Cephalosporin allergy in 15%
What is the treatment for anaphylaxis?
1) Call for help, ABCDE, lie patient flat
2) Oxygen
3) Adrenaline 1:1000 solution, 0.5ml (0.5mg) Intramuscular
4) Repeat in 5 mins if no clinical improvement
5) Antihistamine 10-20mg IM
6) For severe or pt with asthma give hydrocortisone 100-500mg IM, if in shock give 1-2L fluid IV
If the patient is not in anaphylactic shock, what treatment is advisable?
- Antihistamines e.g. cetirizine
- Steroids e.g. prednisolone, hydrocortisone
- Bronchodilators e.g. salbutamol
What are the causes of angioedema?
- Allergic reaction
- C1 inhibitor deficiency (leads to excess bradykinin resulting in swelling)
- Idiopathic/medication related
What is the treatment for C1 esterase deficiency which can cause angioedema?
- Acute attacks = replace enzymes
- Long term = adrenergic steroids and tranexamic acid
- Premedication with C1-esterase-inhibitor concentrate
What is Type IV Hypersensitivity?
Delayed hypersensitivity (48hrs) involving CD4+ and CD8+ T cells ie is T cell mediated
In practice what presentations would make you think your patient was having a Type IV Hypersensitivity reaction?
- Stomatitis
- Lichenoid changes e.g. ulcerations
- Burning mouth syndrome
- Cheilitis and lip swelling
- Chronic facial eruptions
What are the following intraoral metals Type IV hypersensitivity reactions?
a) Gold
b) Palladium
c) Nickel
a) Facial dermatitis, soreness, oral lichenoid reactions
b) Chronic swelling
c) Dermatitis
What do glucocorticoids/corticosteroids supress?
Give 2 examples
Suppression of T cells and decrease TNF alpha, interferon and IL-1 = anti-inflammatory effect
- Hydrocortisone
- Prednisolone
What are the potential complications of glucocorticoid/ corticosteroid treatment?
- Adrenal suppression
- Steroid induced osteoporosis
- Delayed healing
- Increased risk of infection
- Reflux
- Weight gain, unusual hair growth, oedema of feet and ankles
What dosage of prednisolone would cause adrenal suppression in patients?
7.5mg
What are the 3 non-glucocorticoid immunosuppressant drugs?
- Calcineurin inhibitors i.e. ciclosporin and tacrolimus
- Antimetabolites e.g. azathioprine and methotrexate
- Antibodies
How does ciclosporin work?
Reduced T cell responses via inhibition of IL-2
What side effect does ciclosporin
a) cause?
b) is exacerbated by?
c) how is it managed?
a) Gingival overgrowth
b) Nifedipine (calcium channel blocker)
c) Good OH, gingival surgery, reducing dose
Why is tacrolimus used less than ciclosporin?
Risk of carcinoma
How does the immunosuppressant drug azathioprine work and why can it cause oral manifestations?
- Interferes with DNA synthesis and cytotoxic to T cells and B cells (anti-proliferative)
- Depresses bone marrow causing neutropenia, thrombocytopenia and agranulocytosis
How does the immunosuppressant drug methotrexate
a) work?
b) Used for?
c) Side effects?
a) Folic acid analogue inhibiting DNA synthesis (anti-metabolite)
b) Autoimmune diseases e.g. arthritis and in transplantations
c) Bone marrow suppression, liver toxicity (clotting factors)
When is there a need for antibiotic cover in immunosuppressed patients?
When neutrophils <3x10^9 /L
What drugs do you need to be wary of in the treatment of SI-osteoporosis that can cause MRONJ?
Bisphosphonates or Denosumab
Give examples of autoimmunity that is a) organ specific and b) systemic
a) Type 1 diabetes, multiple sclerosis, vitiligo, Crohns disease, Goodpasture’s syndrome
b) Rheumatoid arthritis, SLE, Sjogren’s syndrome, scleroderma
What is Type III sensitivity?
Immune-complex disease, antibodies are generated against a circulating antigen e.g. SLE, rheumatoid arthritis
What is the endocrine autoimmune disease ‘Addison’s disease’?
- Adrenal insufficiency - lack of cortisol
- Addison’s crisis = collapse, abdominal pain and hypotension
- Increased pigmentation, fatigue, depression
What is the endocrine autoimmune disease ‘Type 1 Diabetes Mellitus’?
- Destruction of islets of Langerhans so defective insulin production and hyperglycaemia
- In practice look for Candida/ dry mouth/ sialosis/ glossitis/ hypoglycaemia from missing a meal/ periodontitis
What are the signs of the endocrine autoimmune disease ‘Hypothyroidism’?
- Weight gain
- Hypothermia
- Dry skin
- Cardiac failure
- Anaemia
- Analgesics and sedatives (GA) can precipitate myxoedema coma
What are the signs of the endocrine autoimmune disease ‘Hyperthyroidism’?
- Weight loss
- Diarrhoea
- Anxiety
- Sweating
- Exopthalmus (eyes protrude)
- Careful with carbimazole as can cause agranulocytosis causing oral ulceration
What is the non-endocrine autoimmune disease ‘Coeliac Disease’?
- Gluten sensitivity
- Small intestinal damage including loss of villi, crypt hyperplasia and chronic inflammatory infiltrate causing vitamin deficiency and anaemia
What are the 3 non-endocrine autoimmune haematological diseases?
- Haemolytic anaemia
- Neutropenia (prophylaxis needed with antibaterials/fungals)
- Thrombocytopenic purpura (needs steroids, splenectomy or rituximab)
What are the 2 non-endocrine autoimmune skin conditions?
- Bullous pemphigoid (sub epidermal blisters need prednisolone or azathioprine)
- Pemphigoid vulgaris (non healing blisters need high dose steroids)
What is Goodpasture’s syndrome?
Type II hypersensitivity kidney disease where antibodies bind the glomerular and alveolar basement membrane
What is the systemic autoimmune disease Rheumatoid Arthritis?
Progressive joint destruction, muscle wasting, associated with other diseases such as Sjogren’s syndrome
What are the clinical features of the systemic autoimmune disease Systemic Lupus Erythematosus (SLE)?
- Anaemia
- Bleeding tendencies
- Predisposition to thrombosis
- Oral ulceration, photosensitive rashes, Raynaud’s
- Cardiac, renal and neurological disease (pericarditis, glomerulonephritis)
- Arthritis
Remember for practice steroid therapy and drug reactions with tetracycline
What are the clinical features of the systemic autoimmune disease Limited Scleroderma/ systemic sclerosis?
- Calcinosis
- Raynauds
- Oesophageal immobility
- Sclerodactyly
- Telangiectasia
- Pulmonary hypertension
What are the clinical features of the systemic autoimmune disease Diffuse Scleroderma/ systemic sclerosis?
- Skin changes affecting face and mouth
- Intracutaneous and subcutaneous calcinosis
- Constriction of oral orifice
- Thickened stiffened tongue
- Widening of PDL without tooth mobility
- TMJ involvement with microstomia
- Flexion deformities with hands
What are the clinical features of the systemic autoimmune disease Sjogren’s Syndrome?
- Dry eyes, dry mouth
- Inflammatory arthritis
- Lymphocytic infiltrate of lacrimal and salivary glands
- Candida infection and angular stomatitis
- Non-specific fatigue
- Impaired sense of taste
Remember: GA risk
What are the clinical features of the systemic autoimmune disease Behcet’s Syndrome?
- Aphthous-type oral ulceration
- Genital ulceration
- Iriris (inflammation of eye)
- Pathergy after bloods taken
- Skin lesions: papulopustules, folliculitis, acne, erythema nodosum
What are the side effects of immunosuppressants including steroids
- Oral candidiasis
- Poor wound healing
- Increased risk of infection
- Avoid aspirin and NSAIDS as risk of peptic ulceration
- Altered RBC and WBC counts
- Liver function abnormalities
- Risk of activation of latent viruses
If you see an oral ulcer, what things would you consider could be the underlying cause?
- Herpes simplex
- HPV lesions
- NUP/NUG
- Lymphoma
- Aphthous ulcer from immunodeficiency or anaemia
- CMV
What is a
a) Minor aphthous ulcer
b) Major aphthous ulcer
a) Lasts 7-10 days, painful, heals without scarring
b) Lasts longer and are bigger, heals with scarring
If a pt presents with a swelling on the side of the face and you’ve ruled out trauma, abscess, faceshape etc. what serious problem could it be?
B cell lymphoma
What are the 4 parts of the innate immune response?
Barriers i.e. skin
Soluble/humoral mechanism i.e. enzymes, low pH
Complement
Cells i.e. phagocytes
What is the difference between IgM and IgG?
IgM response fast but not as specific so switches to IgG so specific to pathogen. IgG faster on second infection and more potent.
What are monoclonal antibodies used in the treatment of (immunosuppressant)? What are the complications?
Rheumatoid arthritis
Crohns disease
Psoriasis
ankylosing spondylitis
Risk of infection, increased malignancy risk, hepatic failure
What are the oral problems with immunosuppressants?
Increased risk of opportunistic infections e.g. candida, herpes
Increased risk of malignancies e.g. skin and lip cancer, lymphomas
Increased risk of poor wound healing
Altered red and white cell counts, liver abnormalities
Avoid aspirin and NSAIDs as risk of peptic ulceration
What are the extra-articular manifestations of rheumatoid arthritis? (autoimmune disease)
Muscle wasting
Sjogrens syndrome
GI problems
Felty’s syndrome - splenomegaly and neutropenia
Synovitis and nodules
Vasculitis
