Immunology Flashcards
What are the hallmarks of immune deficiency?
SPUR Serious infections Persistent infections Unusual infections Recurrent infections
What is a primary immunodeficiency disorder?
A disorder characterised by the absence of one or more parts of the immune system.
Which primary immunodeficiencies are most associated with sinusitis and otitis media?
Primary antibody deficiency
Give examples of primary antibody deficiency.
Selective IgA deficiency
Common variable immunodeficiency
Specific antibody deficiency
X-linked agammaglobulinemia
What type of conditions should be considered in patients with laryngeal angioedema?
Complement system disorders
Give an example of a complement system disorder
Hereditary angioedema
What is the most common pulmonary symptom of many primary immune deficiencies?
Pneumonia
True or false? All people suffering from a primary immune deficiency disorder are registered.
True
The united kingdom primary immune deficiency registry (UKPID) serves to track these conditions
What types of pathogens are people suffering from congenital neutropenia more susceptible too?
Bacteria
Fungi
What is Kostmann syndrome?
A severe congenital neutropenia
What are the clinical manifestations of Kostmann syndrome?
Severe chronic neutropenia from birth
Accumulation of precursor cells in the bone marrow
Recurrent bacterial and fungal infections with no pus
What is the treatment for severe congenital neutropenia?
Recombinant G-CSF
A haemopoietic growth factor
What is a recurrent infection with no pus suggestive of?
Severe neutropenia (most likely congenital)
What is Leukocyte adhesion deficiency?
An autosomal recessive immunodeficiency
Causes failure of neutrophil adhesion and migration
What is the clinical picture of leukocyte adhesion deficiency?
Marked leukocytosis and localized bacterial infections
What is Chronic granulomatous disease?
A condition causing the absence of the respiratory burst in phagocytes
Commonly by effecting the NADPH oxidase complex
What are the clinical features of chronic granulomatous disease?
Recurrent deep bacterial infections and recurrent fungal infections
Failure to thrive
Lymphadenopathy and hepatosplenomegaly
Granuloma formation
Briefly explain the IL-12: IFN-gamma network
A mechanism to improve action against intracellular pathogens
Infected macrophages produce IL-12
IL-12 stimulates NK cells and Th1 cells to secrete IFN-gamma
IFN-gamma stimulates macrophages and neutrophils to produce TNF-alpha which stimulates activation of the NADPH oxidase complex
What are the treatments for phagocyte deficiencies?
Immunoglobulin replacement therapy (IVIg)
Aggressive management of infection (PO/IV antibiotics or antifungals, surgical abscess drainage)
Definitive therapy is by a haematopoietic stem cell transplant
Where do mature B cells come from?
The bone marrow (B for Bone)
Where do mature T cells come from?
The thymus (T for Thymus)
What is the normal function of an antibody?
To aid the identification of pathogens by opsonisation
To recruit/activate other aspects of the immune response (e.g complement, phagocytes, NK cells)
Neutralisation of toxins
What is the main group of pathogens antibodies act against?
Bacterias
How are macrophages stimulated?
TH1 cells costimulation with pathogen-derived peptide
IFN-gamma
How are TH0 cells stimulated?
By IL-2 released from TH0 cells
Stimulation of CD4+ T cells through MHC-II presented antigen to T-cell receptors cause differentiation of TH0 cells
How are CD8+ T cells stimulated to cytotoxic T lymphocytes?
MHC-I costimulation by antigen presenting cells leads to differentiation
IL-2 from TH0 cells contributes to this
How are B cells stimulated?
Cytokines + Costimulation from TFH cells along with stimulation of B-cell receptors and opsonin receptors by opsinosided pathogens
What is reticular dysgenesis?
Failure of production of all lymphocytes
Fatal without a haematopoietic stem cell transplant
What is severe combined immunodeficiency?
The failure in the production of lymphocytes
Give the clinical phenotype of combined immunodeficiency.
Unwell by 3 months of age Persistent diarrhoea Failure to thrive All types of infections Unusual skin disease (Graft versus host disease) Family history of early infant death
What is the most common genetic defect in severe combined immunodeficiency?
Common gamma chain (X-linked)
What is the commonest form of severe combined immunodeficiency?
X-linked SCID
45% of all SCIDs
Explain X-linked SCID
Mutation of the IL-2Rgammac gene
(A common element of many cytokine receptors)
Results in the inability to respond to cytokines
Give the clinical phenotype of X-linked SCID
Very low or absent T cells
Normal or increased B cells
Poorly developed lymphoid tissue and thymus
Give the treatment of severe combined immunodeficiency
Prophylactic: Avoid infections (prophylactic antibiotics/antifungals) aggressive treatment of existing infections, antibody replacement therapy
Definitive treatment: Haemopoietic stem cell transplant
What is DiGeorge syndrome?
A failure in production of CD4+ and CD8+ T cells.
Give the phenotype of DiGeorge syndrome.
Development defect of the 3rd/4th pharyngeal pouch
Low set abnormally folded ears, high forehead, cleft palate, small mouth and jaw
Hypocalcaemia
Oesophageal atresia (Incomplete oesophagus)
T cell lymphopenia
Complex congenital heart disease
What type of infection is mostly associated with DiGeorge syndrome?
Viral due to lack of CD4+ and CD8+ T cells
All due to lack of CD4+ T cells
Give the management of DiGeorge syndrome.
Correct metabolic/anatomic abnormalities
Prophylactic antibiotics
Early and aggressive treatment of infections
The possible need for IV immunoglobulin replacement
In DiGeorge syndrome does T cell function improve or worsen with age?
Improve
Suggestive of extra-thymic maturation site of T-cells
What is X-linked agammaglobulinaemia?
An absense of B cells due to a defect in Bruton tyrosine kinase
What is the typical presentation of X-linked agammaglobulinaemia?
Lower and upper respiratory infections, diarrhoea, cellulitis, meningitis and sepsis
Usually due to Gram-positive highly pathogenic encapsulated organism
(Strep.pneumonia, H.influenzae)
Which 2 pathogens are particaully associated with X-linked agammaglobulinaemia?
Streptococci pneumonia
Haemophilus infleunzae
What is Hyper IgM syndrome?
A defect in class-switch recombination resulting in only/effectively only IgM being produced
A severe reduction in serum IgG and IgA
Normal/elevated IgM
Normal B cell numbers
What is meant by class switch recombination?
The change of B-cell differentiation to plasma IgM to another type of Ig
What is Selective IgA deficiency?
A defect in class-switch recombination resulting in a lack of IgA plasma cells (and thus a lack of IgA)
What type of infections are seen in B cell deficiencies?
Recurrent bacterial infection often by very common organisms
What is a hypersensitivity reaction?
The immune response that results in bystander damage to the self
Usually an exaggeration of normal immune mechanisms
(Includes allergies and autoimmunity)
Explain the Gel and Coomb’s classification.
Type I: Immediate hypersensitivity (IgE)
Type II: Direct cell effect
Type III: Immune complex-mediated
Type IV: Delayed-type
What is a Type I hypersensitivity?
An IgE mediated antibody response to an external antigen (AKA allergen)
Give the theory behind the increase in allergic-type hypersensitivity reactions.
The hygiene hypothesis
The hygiene hypothesis poses that an overclean childhood promotes differentiation to Th2 cells leading to the allergic response
What causes stimulation of B-cells to class switch to IgE plasma cells.
IL-4, IL-5, IL-13 from TH2 cells
Explain the mechanism of an allergic reaction.
Sensitisation stage: Mast cells and eosinophils express Fc receptors for IgE antibodies, on the first allergen exposure IgE binds to these Fc receptors and the allergen is cleared.
Allergic stage: When an allergen is re-encountered the allergen binds to the IgE coats causing the release of pre-formed pro-inflammatory mediators
Explain the MoA of a mast cell.
Resident in tissues (especially at the external environment interface)
Produce vasoactive inflammatory substance (Histamine, tryptase, heparin. leukotrienes, prostaglandins and pro-inflammatory cytokines)
What type of pathogen are mast cells particularly useful in?
Mast cells
What are the clinical features of a type I hypersensitivity reaction?
Muscle spasm (e.g bronchoconstriction)
Mucosal inflammation
Inflammatory cell infiltrate
Oedema (Anaphylaxis)
What is a type II hypersensitivity?
A direct cell effect reaction involving IgM or IgG antibodies to the cell surface antigens.
What is the mechanism of a type II hypersensitivity reaction?
Self-reactive antibodies cause:
Activation of the complement
Opsonisation and phagocytosis
Antibody-dependent cellular cytotoxicity via NK cells
Anti-receptor antibodies disturb the normal function of cell surface receptor
Explain Goodpasture’s syndrome
Autoreactive antibodies against the basement membrane [anti-GBM] (TypeII hypersensitivity)
Effects the alveoli and glomeruli
Due to exposure to environmental insult
What is the treatment of Goodpasture’s syndrome
Corticosteroids
Plasmapheresis
Smoking cessation
What is a type III hypersensitivity?
Immune complex-mediated
The presence of immune complexes activated complement and attracts inflammatory cells such as neutrophils
Enzymes from inflammatory cells cause local damage (often at the basement membrane)
Explain the immunology of acute hypersensitivity pneumonitis.
A type III hypersensitivity reaction
Leukocyte accumulation and inflammation within the alveoli
What is the clinical picture of acute hypersensitivity pneumonitis?
Wheeze and malaise 4-8hours post antigen exposure
Possible associated dry cough, pyrexia and breathlessness
O/E often normal
What is the management of type III hypersensitivity reactions?
Avoidance of the causative antigen
Corticosteroids, decrease the inflammation
Immunosuppression, decrease the production of antibodies
Explain type IV hypersensitivity reactions.
Activation of CD4+ T cells and Th1 cells along with macrophages cause damage to tissues.
This is due to antigen exposure directly to cells.
What type of hypersensitivity is sarcoidosis?
Type IV?
Explain the pathogenesis of sarcoidosis.
Inhalation of an antigen stimulates alveolar macrophages along with T cells, this fails to clear leading to persistent immune activation damage and fibrosis.
What is the management of sarcoidosis?
Watching and waiting often goes into spontaneous remission
NSAIDs for acute onset
Systemic corticosteroids to block T cell and macrophage activation
What is autoimmunity?
The presence of immune responses against self-tissue/cells
This can be harmful if the titres of autoreactive antibodies or T cells is high, can also be harmless
What 3 states can T and B cells be when generated in primary lymphoid tissue
Not expressing an antigen-specific receptor
Expressing a non-self antigen-specific receptor (These are good B&T cells)
Expressing a self antigen-specific receptor (These can cause a problem)
Explain central tolerance.
The deletion of self-reactive lymphocytes in primary lymphoid tissues.
Explain peripheral tolerance.
The inactivation of self-reactive lymphocytes in peripheral tissues that escape the central tolerance
What are the major cells of peripheral tolerance
Regulatory T cells (Treg cells)
What are the 2 major cytokines produced by Treg cells?
TGF-beta, IL-10
Explain briefly the pathogenesis of autoimmune disease.
Genetic susceptibility is present
Initiating event leads to break down of immune tolerance to self-antigen
This leads to an autoimmune phenomenon or an autoimmune disease
What is IPEX syndrome?
An X-linked genetic autoimmune disease
Presents in early childhood
Characterised by overwhelming systemic autoimmunity
What are the symptoms of IPEX syndrome?
Severe infections Intractable diarrhoea Eczema Very early onset diabetes mellitus Autoimmune manifestations
What is the treatment of IPEX syndrome?
Hematopoietic stem cell transplantation
Supportive care: immunosuppressive drugs + parenteral nutrition
What are MHC/HLA molecules?
Proteins which express peptides
T cells can only be stimulated by peptides expressed on these molecules
Can be class I or class II
Why are MHC molecules polymorphic?
Allows maintenance of diversity in antigen responsiveness at the population level and at the level of the individual.
Are autoimmune conditions more common in men or women?
Mostly in women
Diabetes mellitus is more common in men
What is a superantigen?
A molecule that can cause MHC receptor stimulation without the presence of an antigen
What is Grave’s disease?
A odd type II hypersensitivity disease
A leading cause of hyperthyroidism
Auto-antibodies are generated that bind to the thyroid stimulating hormone receptor
What type of hypersensitivity is SLE?
type III
What type of hypersensitivity is rheumatoid arthritis?
type IV
