Primary immunodeficiency 2 Flashcards
What are features of the acquired (adaptive) immune system?
- Responsive to an unlimited number of molecules
- Specificity - able to discriminate between very small differences in molecular structure
- Memory - able to recall previous encounter with an antigen and respond more effectively than on the first occasion
What organs/tissues are involved in the adaptive immune response?
Thymus - maturation of T cells
Bone marrow - production of T cells and B cells
Lymph nodes (secondary lymphoid tissues) - sites of activation of T cells and B cells
Where is the thymus located?
Above the heart
Describe the life cycle of a T lymphocyte (4)
- Produced by haematopoetic stem cells in bone marrow
- Immature cells travel to thymus
- In thymus, undergo selection - only 10% cells survive
- Mature T lymphocytes enter circulation
What percentage of T cells mature?
Only around 10% of cells that enter the thymus will exit as mature T cells
What are the functions of T lymphocytes?
- Defence against intracellular pathogens and viruses
* Immunoregulation (T helper)
What are the classifications of T lymphocytes?
CD4 and CD8
What is the function of TH1 cells?
Secrete IFNy that links TH1 cells to macrophages
macrophages then secrete IL-12 which allows for further activation of CD4
What are the functions of CD4+ T lymphocytes? (3)
Immunoregulatory functions
- Provide costimulatory signals - necessary for activation of CD8+ T lymphocytes and naive B cells
- Produce cytokines
- Regulate lymphocytes and phagocytes
How do CD4+ T lymphocytes recognise peptides?
Recognise peptides presented on MHC Class II molecules
What are the functions of CD8+ T cells? (3)
- Kill cells directly via production of pore-forming molecules (e.g. perforin) triggering apoptosis of the target
- Secrete cytokines e.g. IFNγ
- Particularly important in defence against viral infections and tumours
What are CD8+ T cells?
Specialised cytotoxic cells
How do CD8+ T lymphocytes recognise peptides?
Recognise peptides in association with MHC class I molecules
Where are B lymphocytes produced and where do they mature?
- From haemopoetic stem cells in bone marrow
* Mature B lymphocytes found mainly in bone marrow, lymphoid tissue, spleen
What is the function of B lymphocytes? (2)
- Antibody production
* Antigen presentation
Describe the process of the activation of B lymphocytes (6)
- Encounters antigen occur in lymph node
- Appropriate signals provided by T cells, stimulated B cells rapidly proliferate
- Germinal Centre reaction: help from effector TFH cells
- Generate B cells that express receptors of greater affinity than the original
- Generate B cells that express antibodies with different Ig heavy chain constant regions
- Further differentiation (long-lived memory cells and plasma cells which produce antibodies)
What are functions of antibodies? (4)
- IgM and IgD antigen receptors
- Opsonisation – IgG
- Neutralisation – IgA and IgG
- Mast cell activation - IgE
How can the adaptive immune system go wrong? (5)
- Production of immune cells - reticular dysgenesis, severe combined immunodeficiency (SCID)
- Impaired thymus function - DiGeorge syndrome
- Disorders of T cell effector function (failure of signalling, cytokine production)
- Failure of normal apoptosis (autoimmune lymphoproliferative syndromes)
- Failure of HLA expression (no MHC) - Bare lymphocyte syndromes
What is reticular dysgenesis? (4)
Failure of production of:
- Neutrophils
- Lymphocytes
- Monocyte/macrophages
- Platelets
What is the treatment for reticular dysgenesis?
Fatal unless corrected with bone marrow transplantation
What is severe combined immunodeficiency?
Failure of production of lymphocytes
What are the clinical features of SCID? (6)
- Unwell by 3 months of age
- Persistent diarrhoea
- Failure to thrive
- Infections of all types
- Unusual skin disease
- Family history of early infant death
What types of infections do sufferers of SCID contract? (3)
Infections of all types
- Common infections – more severe than usual
- Unusual & opportunistic infections
- Vaccine associated diseases – live attenuated vaccines (immune system not able to cope)
What is the period of the between 3 and 6 months of age where maternal IgG levels drop before complete neonatal production of IgG?
Transient hypogammaglobulinaemia of infancy
How does mother supply infant with antibody protection? (2)
- Active transport of maternal IgG across placenta
- Secretory IgA in colostrum
& breast milk
What are different causes of SCID with regards to T lymphocytes? (4)
- Deficiency of cytokine receptors (req for development and maturation of T cells)
- Deficiency of signalling molecules (block T cell development)
- Metabolic defects (affects metabolism of T cell, affects development)
- Defective receptor rearrangements (cannot create functional antigen binding site)
What is the commonest form of SCID?
X-linked SCID
45% of all severe combined immunodeficiency
What is x-linked SCID? What does it result in? (3)
Mutation of a component of the IL-2 receptor
- Failure of T cell and NK cell development
- Production of immature B cells
- Shrinkage of the thymus
What would a blood count of a SCID individual show? (3)
- Very low or absent T cells (because IL2 is so important for T cell development)
- Normal or increased B cells (not really affected)
- Poorly developed lymphoid tissue and thymus
What is IL-2?
T cell growth factor (activated CD4+ T cells secrete IL-2 to activate other CD4 and CD8 cells)
What is prophylactic treatment for SCID? (5)
Definitive treatment? (2)
Prophylactic treatment
- Prophylactic antibiotics
- Prophylactic antifungals
- No live attenuated vaccines
- Aggressive treatment of existing infections
- Antibody replacement - Intravenous immunoglobulin
Definitive treatment
- Stem cell transplant from HLA identical sibling if possible
- Gene therapy
Explain process of gene therapy for SCID
Stem cells treated ex vivo to express missing component
What is DiGeorge syndrome?
Complex developmental disorder caused by chromosomal deletion at 22q11 - affected gene is usually TBX1
What is TBX1 gene responsible for?
Embryonic development of pharyngeal pouch
What are clinical features of DiGeorge syndrome? (8)
- Developmental defect of 3rd/4th pharyngeal pouch
- Low set ears, abnormally folded ears, high forehead, cleft palate, small mouth and jaw
- Hypocalcaemia
- Oesophageal atresia
- T cell lymphopenia
- Complex congenital heart disease
- Psychiatric disorders (OCD, schizophrenia)
- Developmental delay
What kind of infections are caused by DiGeorge Syndrome? (3)
- Recurrent viral infections
- Recurrent bacterial infections
- Frequent fungal infections
(Why? Answers will be on medblogs)
What will laboratory investigations of DiGeorge syndrome find? (5)
- Absent or decreased number of T cells (defective T cell activation response)
- Normal or increased B cells
- Low IgG, IgA, IgE
- Poor antibody responses to specific pathogens
- Normal NK cells numbers
How is DiGeorge syndrome managed? (4) Why may treatment become less aggressive when older?
- Correct metabolic/cardiac abnormalities
- Prophylactic antibiotics
- Early and aggessive treatment of infection
- Immunoglobulin replacement
- T cell function improves with age
What are disorders of T cell effector function? (3)
Incldude disorders in…
- Cytokine production
- Cytotoxicity
- T-B cell communication
What can cause disorders of T cell effector function?
Infection with mycobacteria
affects IL-12: IFNy network
What can infection with mycobacteria result in?
Affects IL-12: IFNy network
Normally…
* Infected macrophages stimulated to produce IL-12
* IL-12 induces T cells to secrete IFNγ
* Then IFNγ feeds back to macrophages and neutrophils
* Stimulates production of TNF
* Activates NADPH oxidase
What deficiencies can cause disorders of T cell effector function? (4)
Deficiencies in: * IL-12 * IL-12 receptor * IFNγ * IFNγ receptor (result in increases susceptibility to infection)
What types of infection can cause disorders of T cell effector function? (4)
- Tuberculosis
- Atypical mycobacteria
- BCG infection after immunisation
- Deep fungal infections e.g. aspergillus
What are clinical features of T cell deficiencies? (4)
- Recurrent infections (viral, fungal, bacterial, intracellular pathogens e.g. mycobacteria)
- Opportunistic infections
- Malignancies at young age
- Autoimmune disease
What are first line investigations of T cell deficiencies? (3) Second line? (4)
First line investigations
- Total white cell count
- Quantitation of lymphocyte subpopulations
- Serum immunoglobulins (marker of functional T cells)
Second line investigations
- Functional tests of T cell activation and proliferation
- Additional tests of lymphocyte lineage
- A HIV test is ESSENTIAL
What are B cell maturation defects? (5)
- Failure of lymphocyte precursors: Severe combined immune deficiency
*Failure of B cell maturation: Bruton’s X-linked hypogammaglobulinaemia - Failure of production of IgG antibodies:
Common variable immune deficiency, selective antibody deficiency - Failure of TFH cell costimulation
- Failure of IgA production: selective IgA deficiency
What are common variable immune deficiencies?
Heterogenous group of disorders - disease mechanism unknown
What are clinical features of common variable immune deficiency?
- Recurrent bacterial infections - often with severe end-organ damage (e.g. bronchiectasis, persistent sinusitis, recurrent gastrointestinal infection)
- Autoimmune disease
- Granulomatous disease
What are clinical features of B cell deficiencies?
- Recurrent infections (primarily bacterial infections, often very common organisms)
- Opportunistic infections
- Antibody-mediated autoimmune disease
What do investigations of B cell deficiencies involve?
First line investigations
- Total white cell count and differential
- Serum/urine immunoglobulins
Second line investigations
- Quantitation of B and T lymphocytes
- Specific antibody responses to known pathogens
How are B cell deficiencies managed?
- Aggressive treatment of infection
- Immunoglobulin replacement
- Stem cell transplantation in some situations
find annotated version of investigation of primary antibody deficiencies
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