Primary Immunodefficiency 2 Flashcards
What are components of the adaptive immune system?
T lymphocytes:
- CD4 T cells
- CD8 T cells
B lymphocytes:
- B cells
- Plasma cells
- Antibodies
Soluble components:
- Cytokines and chemokines
What are the primary lymphoid organs?
Organs involved in lymphocyte development
Bone marrow: Both T and B lymphocytes are derived from haematopoetic stem cells, Also the site of B cell maturation.
Thymus: Site of T cell maturation. Most active in the foetal and neonatal period, involutes after puberty.
What do defects in haemopoetic stem cells result in?
Reticular dysgenesis: Most severe form of severe combined immunodeficiency (SCID). Due to a mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2).
Failure of production of:
- Lymphocytes
- Neutrophils
- Monocyte/macrophages
- Platelets
Fatal in very early life unless corrected with bone marrow transplantation
What do failures in lymphoid precursors result in?
Other forms of severe combined immunodeficiency (SCID).
What are the causes of severe combined immunodeficiency?
>20 possible pathways identified.
- Deficiency of cytokine receptors
- Deficiency of signalling molecules
- Metabolic defects: Effect on different lymphocyte subsets (T, B, NK) depend on mutation.
What is X-Linked SCID?
45% of all severe combined immunodeficiency. Mutation of common gamma chain on chromosome Xq13.1.
Shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells.
Phenotype: Very low or absent T cell numbers. Very low or absent NK cell numbers. Normal or increased B cell numbers but low Igs.
What is ADA deficiency?
16.5% of all severe combined immunodeficiency:
Adenosine Deaminase Deficiency:
Enzyme required for cell metabolism in lymphocytes.
Phenotype: Very low or absent T cell numbers. Very low or absent B cell numbers. Very low or absent NK cell numbers.
What protects SCID neonates in the first 3 months of life?
Active transport of maternal IgG across placenta
IgG in colostrum
What is the clinical phenotype of severe combined immunodeficiency?
- Unwell by 3 months of age
- Infections of all types
- Failure to thrive
- Persistent diarrhoea
- Unusual skin disease: Colonisation of infant’s empty bone marrow by maternal lymphocytes. Graft versus host disease.
- Family history of early infant death
How do T-cells mature?
Arise from haematopoetic stem cells. Exported as immature cells to the thymus where undergo selection. Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs.
How are T-cells selected?
Low affinity for HLA: Not selected to avoid inadequate reactivity
Intermediate affinity for HLA: Positive selection ~10% original cells
High affinity for HLA: Negative selection to avoid autoreactivity
How are CD4+ and CD8+ cells selected?
Intermediate affinity for HLA class I: Differentiate as CD8+ T cell
Intermediate affinity for HLA class II: Differentiate as CD4+ T cell
What are CD8+ cells?
Specialised cytotoxic cells. Recognise peptides derived from intracellular proteins in association with HLA class I – HLA-A, HLA-B, HLA-C.
Kill cells directly – Perforin (pore forming) and granzymes.
Expression of Fas ligand.
Secrete cytokines eg IFNg TNFa
Particularly important in defence against viral infections and tumours.
What are CD4+ cells?
Recognise:
- Peptides derived from extracellular proteins
- Presented on HLA Class II molecules (HLA-DR, HLA-DP HLA-DQ).
Immunoregulatory functions via cell:cell interactions and expression of cytokines.
Provide help for development of full B cell response.
Provide help for development of some CD8+ T cell responses.
What are subsets of CD4+ cells?
Th1: Help CD8+ T cells and macrophages
Th17: Help neutrophil recruitment
Treg: IL-10/TGF beta expressing CD25+ Foxp3+
TFh: Follicular helper T cells
Th2: Helper T cells
TPh: Peripheral helper T cells
What do defects in T cell maturation and selection in the thymus result in?
22q11.2 deletion syndrome: DiGeorge syndrome
Developmental defect of pharyngeal pouch
- Deletion at 22q11.2
- TBX1 may be responsible for some features
- Usually sporadic rather than inherited
What are the features of a patient with DiGeorge Syndrome?
High forehead
Low set, abnormally folded ears cleft palate, small mouth and jaw
Hypocalcaemia
Underdeveloped thymus
Complex congenital heart disease
What are the clinical features of DiGeorge Syndrome?
- Normal numbers B cells
- Reduced numbers T cells
- Proliferation with age
- Immune function usually only mildly impaired and improves with age
What is bare lymphocyte syndrome type 2?
Defect in one of the regulatory proteins involved in Class II gene expression:
- Regulatory factor X
- Class II transactivator
Absent expression of MHC Class II molecules. Profound deficiency of CD4+ cells:
- Usually have normal number of CD8+ cells
- Normal number of B cells
- Low IgG or IgA antibody due to lack of CD4+ T cell help
BLS type 1 also exists due to failure of expression of HLA class I
What is the clinical phenotype of bare lymphocyte syndrome?
Unwell by 3 months of age
Infections of all types
Failure to thrive
Family history of early infant death
What are disorders of T cell effector function?
Cytokine production – IFN
Cytokine receptors – IL12 receptor
Cytotoxicity
T-B cell communication
What are clinical features of T cell deficiency?
Viral infections: Cytomegalovirus
Fungal infection: Pneumocystis, Cryptosporidium
Some bacterial infections, especially intracellular organisms: Mycobacteria tuberculosis, Salmonella
Early malignancy
What are investigations of T cell deficiency?
Total white cell count and differential: Remember that lymphocyte counts are normally much higher in children than in adults.
Lymphocyte subsets: Quantify CD8 T cells, CD4 T cells as well as B cells and NK cells.
Immunoglobulins: If CD4 T cell deficient.
Functional tests of T cell activation and proliferation: Useful if signalling or activation defects are suspected.
HIV test.
What is the management of immunodeficiency involving T cells?
Aggressive prophylaxis/treatment of infection.
Haematopoieitic stem cell transplantation: To replace abnormal populations in SCID. To replace abnormal cells - class II deficient APCs in BLS.
Enzyme replacement therapy: PEG-ADA for ADA SCID.
Gene therapy: Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo.
Thymic transplantation: To promote T cell differentiation in Di George syndrome. Cultured donor thymic tissue transplanted to quadriceps muscle.
How are B cells selected?
No recognition of self in bone marrow: Survive
Recognition of self In bone marrow: Negative selection to avoid autoreactivity
What is notable about early IgM response?
It is T cell independent.
What is particular about germinal centre reaction in lymph node?
It is CD4+ T cell dependent
- Dendritic cells prime CD4+ T cells
- CD4+ T cell help for B cell differentiation Requires CD40L:CD40B cell proliferation.
- Somatic hypermutation: Isotype switching to IgG, A , E
What is the structure of immunoglobulins?
Soluble proteins made up of two heavy and two light chains:
- Heavy chain determines the antibody class
- IgM, IgG, IgA, IgE, IgD
- Subclasses of IgG and IgA also occur
Antigen is recognised by the antigen binding regions (Fab) of both heavy and light chains. Effector function is determined by the constant region of the heavy chain (Fc).
What is the function of antibodies?
Identification of pathogens and toxins (Fab mediated).
Interact with other components of immune response to remove pathogens (Fc mediated):
- Complement
- Phagocytes
- Natural killer cells
Particularly important in defence against bacteria of all kinds.
What is Bruton’s X linked agammaglobulinaemia?
Abnormal B cell tyrosine kinase (BTK) gene Pre B cells cannot develop to mature B cells.
Absence of mature B cells.
No circulating Ig after ~ 3 months.
What is the clinical phenotype of Bruton’s X linked agammaglobulinaemia?
Boys present in first few years of life
Recurrent bacterial infections: Otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis
Viral, fungal, parasitic infections: Enterovirus, Pneumocystis
Failure to thrive
What can B cell maturation defects result in?
Hyper IgM syndrome (X-linked recessive)
Which mutation causes Hyper IgM syndrome?
Mutation in CD40 ligand gene (CD40L, CD154)
- Member of TNF Receptor family
- Encoded on Xq26
- Involved in T-B cell communication
- Expressed by activated T cells
- NOT on B cells
What are the features of hyper IgM syndrome?
- Normal number circulating B cells
- Normal number of T cells but activated cells do not express CD40 ligand
- No germinal centre development within lymph nodes and spleen
- Failure of isotype switching
- Elevated serum IgM
- Undetectable IgA, IgE, IgG
What is the clinical phenotype of hyper IgM syndrome?
Boys present in first few years of life
Recurrent infections - bacterial
Subtle abnormality in T cell function predisposes to Pneumocystis jiroveci infection, autoimmune disease and malignancy
Failure to thrive
What is common variable immune deficiency?
Heterogenous group of disorders. Many different genetic defects – many unidentified. Failure of full differentiation/function of B lymphocytes.
What is common variable immune deficiency defined by?
Marked reduction in IgG, with low IgA or IgM.
Poor/absent response to immunisation. Recurrent bacterial infections. Absence of other defined immunodeficiency.
What are the clinical features of common variable immune deficiency?
Recurrent bacterial infections
- Pneumonia, persistent sinusitis, gastroenteritis
- Often with severe end-organ damage – Pulmonary disease
Interstitial lung disease
- Granulomatous interstitial lung disease (also LN, spleen)
- Obstructive airways disease
Gastrointestinal disease
- Inflammatory bowel like disease
- Sprue like illness
- Bacterial overgrowth
Autoimmune disease
- Autoimmune haemolytic anaemia or thrombocytopenia
- Rheumatoid arthritis
- Pernicious anaemia
- Thyroiditis
- Vitiligo
Malignancy
- Non-Hodgkin lymphoma
What is selective IgA deficiency?
Prevalence = 1:600
2/3rd individuals asymptomatic, 1/3rd have recurrent respiratory tract infections.
Genetic component, but cause as yet unknown.
What are clinical features of lymphocyte deficiency?
Antibody deficiency (or CD4 T cell deficiency).
Bacterial infections: Staphylococcus, Streptococcus
Toxins: Tetanus, Diptheria
Some viral infections: Enterovirus
What are investigations of B cell deficiencies?
Total white cell count and differential: Remember that lymphocyte counts are normally much higher in children than in adults.
Lymphocyte subsets: Quantify B cells as well as CD4 T cells, CD8 T cells and NK cells.
Serum immunoglobulins and protein electrophoresis: Production of IgG is surrogate marker for CD4 T cell helper function.
Functional tests of B cell function: Specific antibody responses to known pathogens/immunisations - measure IgG antibodies against tetanus, Haemophilus influenzae B and S. pneumoniae.
If specific antibody levels are low, immunise with the appropriate killed vaccine and repeat antibody measurement 6–8 weeks later.
What is the management of immunodeficiency involving B cells?
Aggressive prophylaxis/treatment of infection.
Immunoglobulin replacement if required:
- Derived from pooled plasma from thousands of donors.
- Contains IgG antibodies to a wide variety of common organisms.
- Aim of maintaining trough IgG levels within the normal range.
- Treatment is life-long.
Immunisation:
- For selective IgA deficiency.
- Not otherwise effective because of defect in IgG antibody production.
