Immunology Flashcards
Hallmarks of immunodeficiency
Serious infections
Persistent infections
Unusual infections
Recurrent infections
Features suggestive of primary immune deficiency
Weight loss or failure to thrive Severe skin rash (eczema) Chronic diarrhoea Mouth ulceration Unusual autoimmune disease Family history
Primary immunodeficiency
Rare
Hereditary
Secondary
Common
Acquired
Often subtle
Often involves more than one component of immune system
Conditions associated with secondary immune deficiency
Ageing, Prematurity Infection Treatment interventions Malignancy Biochemical and nutritional disorders
Phagocyte Deficiencies
Defects of phagocyte production, mobilisation and recruitment
Leukocyte Adhesion Deficiency
Defects of recognition
Failure of oxidative killing mechanisms
Failure of stem cells to differentiate into neutrophils
Primary defect: Recticular Dysgenesis
Secondary defect: After stem cell transplantation
Failure of neutrophil maturation
Kostmann syndrome
Cyclic neutropaenia
Recticular dysgenesis
Complete block in leukocyte development
Severe Combined Immuno Deficiency
Kostmann Syndrome
Defect in receptor or cytokine GCSF
Blocks neutrophil development
Autosomal recessive disorder
Severe chronic neutropaenia
Supportive treatments for kostmann syndrome
Prophylactic antifungals
Prophylactic antibiotics
Definite treatments for kostmann syndrome
Stem Cell transplantation
Granulocyte Colony Stimulating Factor
Leukocyte adhesion deficiency
Rare primary immunodeficiency
Caused by genetic defect in leukocyte integrins (CD18)
Failure to recognise activation markers expressed on endothelial cells
Markers of leukocyte adhesion deficiency
Localised deep tissue bacterial infections that are difficult to detect
Very high neutrophil count
Failure of oxidative killing mechanisms
Absent respiratory burst
Deficiency of the intracellular killing mechanism of phagocytes
Inability to generate oxygen free radicals
Failure to degrade chemoattractants and antigens
Persistent accumulation of neutrophils, activated macrophages and lymphocytes
Features of chronic granulomatous disease
Recurrent deep bacterial infections Recurrent fungal infections Failure to thrive Lymphadenopathy and hepatosplenomegaly Granuloma formation
Laboratory investigation of chronic granulomatous disease
NBT Test
Treatment of chronic granulomatous disease
Prophylactic antibiotics
Prophylactic antifungals
Stem cell transplantation
Gene therapy
Investigations in phagocyte recruitment function
Full blood count & differential
Presence of pus
Expression of neutrophil adhesion molecules
Investigations in phagocyte recognition function
Chemotactic assays
Phagocytosis assays
Investigations in phagocyte killing function
NBT test of oxidative killing
What drives immunoglobulin class switching?
CD4 cell
What is the first antibody secreted from the bone marrow?
IgM
Antibody functions
Antigen receptors (IgM and IgD)
Opsonisation (IgG)
Neutralisation (IgA)
Mast cell activation (IgE)
How can the adaptive immune system go wrong?
Defects of hematopoietic stem cells
Defects of lymphoid precursors (SCID)
Failure of Thymic development
Disorders of T cell effector function
Clinical phenotype of severe combined immunodeficiency
Unwell by 3 months of age Persistent diarrhoea Failure to thrive Infection of all types Unusual skin disease Family history of early infant death
Causes of SCID
Deficiency of cytokine receptors
Deficiency of signalling molecules
Metabolic defects
Defective receptor arrangements
X-linked SCID
Mutation of a component of the IL-2 Receptor
Results in inability to respond to cytokines
-Failure of T cell and NK cell development
-Production of immature B cells
DiGeorge Syndrome
Failure of thymic development
Results in T cell immunodeficiency
Phenotype of DiGeorge Syndrome
Congenital heart defects Cleft palate Hypocalcaemia Developmental delay Psychiatric disorders Oesophageal atresia T cell lymphopaenia
Laboratory results for DiGeorge Syndrome
Absent or decreased number of T cells
Normal or increased B cells
Normal NK cells numbers
Disorders of T cell effector function
Cytokine production
Cytotoxicity
T-B cell communication
(IFNy deficiency, IL-12 deficiency)
First line investigations of T cell deficiencies
Total white cell count and differential
Quantitation of lymphocyte subpopulations
Serum immunoglobulins
Second line investigations of T cell deficiencies
Functional tests of T cell activation and proliferation
Additional tests of T lymphocyte lineage
HIV test
Immune deficiencies affecting B lymphocytes
B cell maturation defects
Failure of TFH cell co-stimulation
Failure of IgA production (Selective IgA deficiency)
Failure of production of IgG (Common variable immune deficiency, Selective antibody deficiency)
First line investigations of B cell deficiencies
Total white cell count and differential
Serum/ urine immunoglobulins
Second line investigations of B cell deficiencies
Quantitation of B and T lymphocytes
Specific antibody responses to known pathogens
Hypersensitivity Reaction
Immune response that results in bystander damage to the self
Usually exaggeration of normal immune mechanisms
Type 1 Hypersensitivity reaction
Immediate hypersensitivity
Type 2 hypersensitivity reaction
Direct cell killing
Type 3 hypersensitivity reaction
Immune complex mediated
Type 4 hypersensitivity reaction
Delayed type hypersensitivity
What type of hypersensitivity reaction is allergic reaction?
Type 1: Immediate hypersensitivity
Allergy
IgE-mediated antibody response to external antigen
The ‘Hygiene Hypothesis’
Changes in microbial stimuli influences the maturation of the immune response
General decrease in infectious burden during early life
results in increased predisposition to allergic conditions during childhood
Vasoactive substances produced by mast cells
Histamine, Tryptase, Heparin
Leukotrienes, prostaglandins
TNFa, IL-4
The role of mast cells in allergic reactions
Express receptors for Fc region of IgE antibody on their surface
Release of vasoactive mediators (histamine, tryptase)
Increased cytokine and leukotriene transcription
Mast cell stabilisers
Sodium cromoglycate
Stabilises mast cell membranes
Prevents release of inflammatory mediators
Anti-histamine
H1 Receptor antagonists
Block biological effects of histamines
Leukotriene receptor antagonists
Montelukast
Blocks effects of leukotrienes
Adrenaline
Acts on B2 adrenergic receptors to constrict arterial smooth muscle
Pathophysiology of direct cell killing (type 2)
Antibody binds to cell surface antigen
Results in activation of complement and opsonisation
Functions of antibody
Activates B lymphocytes
Acts as opsonins
Mast cell degranulation
Causes antigen clumping and inactivation of bacterial toxins
Activates antibody dependent cellular activity
Activates complement
Effects of complement activation
Chemotaxis
Solubilization of immune complexes
MAC-direct killing of bacteria
Opsonisation
Which fragments of complement proteins released after activation increase permeability of blood vessels
Anaphylotoxins (C3a and C5a)
Clinical examples of type 2 hypersensitivity
Acute haemolytic transfusion reaction
Drug induced haemolysis
Blood type A
Surface antigen A
Anti-B antibodies
Blood type B
Surface antigen B
Anti-A antibodies
Blood type AB
Surface antigen A and B
Neither anti-A or anti-B antibodies
Type O
Neither surface A or B antigens
Anti- A and anti-B antibodies
Type 2 hypersensitivity management
Plasmapheresis
Immunosuppression
Pathophysiology of type 3 hypersensitivity
Antibodies bind to soluble antigens forming small immune complexes
These are trapped in small blood vessels, joints and glomeruli
Management of type 3 hypersensitivity reaction
(Avoidance)
Corticosteroids to reduce inflammation
Immunosuppression to decrease production of antibody
Autoimmune diseases associated with delayed hypersensitivity reaction
Type 1 diabetes
Psoriasis
Rheumatoid arthritis
Non-autoimmune diseases associated with delayed hypersensitivity reaction
Contact dermatitis Tuberculosis Leprosy Sarcoidosis Cellular rejection of organ transplant
Pathophysiology of type 4 hypersensitivity reaction
Initial sensitisation to antigen creates ‘primed’ generation of effector Th1 and memory T cells
Subsequent exposure activates previously primed T cells
Recruitment of macrophages, lymphocytes, neutrophils, proteolytic enzymes, inflammation…
Management of type 4 hypersensitivity reaction
Watchful waiting
NSAIDS
Systemic corticosteroids
