Primary Immune Deficiencies 2 Flashcards
What IG is the first to be produced
IgM
IgG, E and A are produced thereafter
What is reticular dysgenesis
Most severe form of severe combined immunodeficiency (SCID)
It is a defect of haematopoietic stem cells
Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2
Results in failure of production of: lymphocytes, neutrophils, monocytes/macrophages, platelets
Fatal in very early life unless corrected with bone marrow transplantation
Causes of severe combined immunodeficiency
> 20 possible pathways identified:
Deficiency of cytokine receptors
Deficiency of signalling molecules
Metabolic defects
Has effects on different lymphocyte subsets (T, B, NK) depend on the exact mutation
What is X-linked SCID
45% of all severe combined immunodeficiency
Mutation of gamma chain of IL2 receptor on chromosome Xq13.1 :
Shared by receptor for IL2, IL4, IL7, IL9, IL15 and IL21
Inability to respond to cytokines causes early arrest of T cell and natural killer cell development and production of immature B cells.
Phenotype:
Very low or absent T cell numbers
Very low of absent NK cell numbers
Normal or increased B cell numbers but low Igs.
Phenotypes of X-linked SCIDs
Very low or absent T cell numbers
Very low of absent NK cell numbers
Normal or increased B cell numbers but low Igs.
Adenosine Deaminase Deficiency (ADA)
16.5% of all severe combined immunodeficiency
Autosomal recessive
ADA: enzyme required for cell metabolism in lymphocytes
ADA deficiency: accumulation of adenosine, 2 deoxyadenosine –> deoxyadenosine triphosphate is toxic to lymphocytes
Phenotype:
Very low or absent T cell numbers
Very or absent B cell numbers
Very low of absent NK cell numbers
ADA deficiency phenotype
Very low or absent T cell numbers
Very or absent B cell numbers
Very low of absent NK cell numbers
Clinical presentation of SCIDs
Unwell by 3 months of age
Infections of all types occur: Candida and diarrhoea common early features
Bacterial, viral, fungal, protozoal infections occur
Failure to thrive
Unusual skin disease: colonisation of infant’s empty bone marrow by maternal lymphocytes, graft versus host disease
Family history of early infant death
What protects the SCID neonate in the first 3 months of life
Active transport of maternal IgG across placenta before birth
IgG in colostrum
T lymphocyte maturation
Arise from haematopeietic stem cells
Exported as immature cells to the thymus where they undergo selection
Mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
How do T cell receptors recognise HLA/peptide complexes
CD8+ T cells recognise peptide presented by HLA class 1 molecules on APCs CD4+ T cells recognise peptide presented by HLA class 2 molecules. on APCs
T cells with low affinity for HLA
Not selected to avoid inadequate reactivity
T cells with intermediate affinity for HLA
Positive selection - approximately 10% of original cells
T cells with high affinity for HLA
Negative selection to avoid autoreactivity
Intermediate affinity for HLA class 1
Differentiate as CD8+ T cells
Intermediate affinity for HLA class 2
Differentiate as CD4+ T cells
Features of CD8+ cytotoxic T 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 do CD8+ cytotoxic T cells protect against
Particularly important in defence against viral infections and tumours
What do CD8+ cytotoxic T cells secrete
IFNg
TNFa
Functions of CD4+ helper T cells
Recognise peptides derived from extracellular proteins They recognise peptides presented on HLA class 2 moleculoes (HLA-DR, HLA-DP, HLA-DQ)
Immunological 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
Function of Th1 CD4+ T cells
Help CD8 T cells and macrophages
What do Th1 CD4+ T cells secrete
IL2
INFg
TNFa
IL10
Function of CD4+ Th17 T cells
Help neutrophil recruitment
What do CD4+ Th17 T cells secrete
IL17
IL21
IL22
What do Treg CD4+ T cells secrete
IL10
Foxp3
CD25
Function of Treg CD4+ T cells
IL10/TGF beta expressing CD25+Foxp3+
Function of TFh CD4+ T cells
Follicular helper T cells
What do TFh CD4+ T cells secrete
IL2
IL10
IL21
Function of Th2 CD4+ T cells
Helper T cells
What do Th2 CD4+ T cells secrete
IL4
IL5
IL13
IL10
Where are T cells primed
Thymus gland
Where are T cells produced
Pre T cells produced in bone marrow
Proliferation and positive and negative selection of T cells occurs in thymus gland
Export of mature T lymphocytes to periphery
What is DiGeorge syndrome
22q11.2 deletion syndrome
Developmental defect of pharyngeal pouch
TBX1 may be responsible for some features
Usually sporadic rather than inherited
Normal numbers of B cells
Reduced numbers of T cells
Homeostatic proliferation with age
Immune function usually only mildly impaired and improves with age
Clinical features of DiGeorge syndrome
High forehead Low set, abnormally folded ears Cleft palate, small mouth and jaw Hypocalcaemia Oesophageal atresia Underdeveloped thymus (reduced number of T cells) Immune function only mildly impaired and improves with age Complex congenital heart disease
What is involved in MCH class 2 selective CD4+ T lymphocyte development
Double positive CD4+8+ thymocytes are selected for to produce single positive CD4+ lymphocytes.
Active selection of cells that recognise peptides in conjunction with MHC class 2
What is bare lymphocyte syndrome - type 2
Three types of defects:
Defect in one of the regulatory proteins involved in Class 2 gene expression: regulatory factor X, class II transactivator
Absent expression of MHC class 2 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 1
Clinical phenotype presentation of BLS
Unwell by 3 months of age
Infections of all types: bacterial, viral, fungal, protozoal
Failure to thrive
Family history of early infant death
Disorders of T cell effector function
Cytokine production - IFN
Cytokine receptors - IL12R
Cytotoxicity
Summary of types of T cell defects
Failure of lymphocyte precursors: severe combined immune deficiency (X-linked SCID)
Failure of thymic development: 22q11.2 syndromes (DiGeorge syndrome)
Failure of expression of HLA molecules: BLS.
Failure of signalling, cytokine production and effector functions: IFNg or receptor deficiency, IL12 or receptor deficiency.
Clinical features of T lymphocyte deficiency
Especially vulnerable to intracellular pathogens
Viral infections (CMV)
Some bacterial infections (Mycobacteria tuberculosis, salmonella, listeria)
Some parasitic infections (toxoplasma)
Fungal infection (PCP)
Early malignancy
CD4 deficiency will impact on development of T cell dependent antibody responses
Investigations for T cell deficiencies
Total WCC 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 cell and NK cells
Immunoglobulins - If CD4 T cell deficiency
Functional tests of T cell activation and proliferation - useful if signalling or activation defects are suspected
HIV test
Low CD4 T cells Low CD8 T cells Low NK cells Normal or low B cells Normal or low IgM Low IgG
X linked SCID
X-linked SCID
Low CD4 T cells Low CD8 T cells Low NK cells Normal or low IgM Low IgG
Low CD4 T cells Low CD8 T cells Normal NK cells Normal B cells Normal or low IgG
DiGeorge syndrome
DiGeorge syndrome
Low CD4 T cells Low CD8 T cells Normal NK cells Normal B cells Normal IgM Normal or low IgG
Low CD4 T cell Normal CD8 T cell Normal NK cells Normal B cells Normal IgM Low IgG
BLS type 2
BLS type 2
Low CD4 T cell Normal CD8 T cell Normal NK cells Normal B cells Normal IgM Low IgG
Management of immunodeficiency involving T cells
Aggressive treatment/prophylaxis of infection
Haematopoietic stem cell transplant: to replace abnormal populations in SCID and 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 DiGeorge syndrome, cultured donor thymic tissue transplanted to quadriceps muscle.
Severe recurrent infections from 3 months,CD4 and CD8 T cells absent, NK cells absent, B cell present, Igs low. Normal facial features and cardiac echocardiogram
X-linked SCID
Young adult with chronic infection with Mycobacterium marinum
IFNg receptor deficiency
Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
DiGeorge syndrome
6 month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG low
Bare lymphocyte syndrome type 2
B cells with no recognition of self in bone marrow
Survive
B cells with recognition of self in bone marrow
Negative selection to avoid autoreactivity
B cell response to antigen encounter
Early IgM/T cell independent response results in IgM secreting plasma cells
Germinal centre reaction in the lymph node - dependent on CD4+ T cells:
Dendritic cells prime CD4+ T cells
CD4+ T cells help for B cell differentiation. Required CD40L:CD40
B cell proliferation - somatic hypermutation and isotype switching to IgG, A and E
Results in high affinity B memory cells and IgG, IgA, IgE secreting plasma cells.
What are 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)
Single chain Igs
IgG
IgD
IgE
Dimeric Igs
IgA
Pentameric Ig
IgM
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
Bruton’s X-linked hypogammaglobulinaemia
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 approximately 3 months
Clinical presentation of Bruton’s X-linked a-gammaglobulinaemia
Boys present in first few years of life
Recurrent bacterial infections are most important: Haemophilus influenza, Streptococcus pneumonia and pyogenes, Pseudomonas species
Otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis
Viral, fungal, parasitic infections: Enteroviral infection
Failure to thrive
B cell maturation defect
Hyper IgM syndrome
Hyper IgM syndrome
Class switch recombination defects
E.g. Mutation in CD40L gene (X-linked): member of the TNF receptor family, encoded on Xq26, involved in T-B cell communication, expressed by activated T cells - not on B cells.
Features of hyper IgM syndrome - CD40L deficiency
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
Low IgA, IgE, IgG
Clinical presentation of X-linked hyper IgM
Boys present in first few years of life
Recurrent bacterial infections: Haemophilus influenza, Streptococcus pneumonia and pyogenes, Pseudomonas species
Otitis media, sinusitis, pneumonia
Parasite: Cryptosporidium, Diarrhoea
Subtle abnormality in T cell function predisposes to Pneumocystis jiroveci infection, autoimmune disease and malignancy
Failure to thrive
Common variable immune deficiency
Low IgG, IgA and IgE
Recurrent bacterial infections
Cause unknown
Features of common variable immune deficiency
Heterogenous group of disorders
Many different genetic defects – most unidentified
Failure of differentiation/ function of B lymphocytes
Defined by:
Marked reduction in IgG, with low IgA or IgM
Poor/absent response to immunisation
Absence of other defined immunodeficiency
Clinical features of common variable immune deficiency in adults and children
Recurrent bacterial infections: Often with severe end-organ damage, Pneumonia, persistent sinusitis, gastroenteritis
Pulmonary disease: Obstructive airways disease, Interstitial lung disease, Granulomatous interstitial lung disease (also LN, spleen)
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
Selective IgA deficiency
Complete deficiency of IgA affects 1:600 caucasoid individuals
Genetic and environmental factors important in development
Associated with recurrent respiratory and gastrointestinal tract infections in 30%
Summary of B cell maturation defects
Failure of lymphocyte precursors: severe combined immune deficiency
Failure of B cell maturation: Bruton’s X-linked agammaglobulinaemia
Failure of T cell costimulation: X-linked hyper IgM syndrome
Failure of IgA production: selective IgA deficiency
Failure of production of IgG antibodies: common variable immune deficiency, selective antibody deficiency
Clinical features of lymphocyte deficiencies
Antibody deficiency (or CD4 T cell deficiency):
Bacterial infections: encapsulated bacteria (e.g. haemophilus influenza, streptococcus pneumonia and pyogenes, pseudomonas species.
Some viral infections: enterovirus
Toxins: tetanus, diphtheria
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
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
Functional tests have generally superceded IgG subclass quantitation.
Normal CD4 T cells Normal CD8 T cells Low B cells Low IgM Low IgG Low IgA
Bruton’s X-linked
Bruton’s X-linked
Normal CD4 T cells Normal CD8 T cells Low B cells Low IgM Low IgG Low IgA
Normal CD4 T cells Normal CD8 T cells Normal B cells Raised IgM Low IgG Low IgA
Hyper IgM X-linked
Hyper IgM X-linked
Normal CD4 T cells Normal CD8 T cells Normal B cells Raised IgM Low IgG Low IgA
Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Normal IgG Low IgA
Selective IgA deficiency
Selective IgA deficiency
Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Normal IgG Low IgA
Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Low IgG Normal or low IgA
CVID
CVID
Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Low IgG Normal or low IgA
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
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
Common variable immunodeficiency
Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, high IgM, absent IgA and IgG
X-linked hyper IgM syndrome due to CD40L mutation
1 year old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent
Bruton’s X-linked hypogammaglobulinaemia
Recurrent respiratory tract infections, absent IgA, normal IgM and IgG
IgA deficiency
Phagocyte immunodeficiencies
Kostmann syndrome
Leukocyte adhesion deficiency
Chronic granulomatous disease
Natural killer cells immunodeficiency
Classical NK deficiency
Functional NK deficiency
Complement immunodeficiencies
Classical pathway deficiencies MBL deficiency Alternative pathway deficiencies C3 deficiency Terminal pathway deficiencies
Cytokine immunodeficiencies
IL12 and IL12 receptor deficiency
IFNg and IFNg receptor deficiency
Haematopoietic stem cells immunodeficiencies
Reticular dysgenesis
Lymphoid precursors immunodeficiencies
Severe combined immunodeficiency
T cell immunodeficiencies
22q11.2 deletion syndromes
Bare lymphocyte syndrome
B cell immunodeficiencies
Bruton X-linked agammaglobulinaemia
X-linked hyperIgM syndrome
Common variable immunodeficiency
IgA deficiency
