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.
