Primary Immune deficiency 2 Flashcards
What are the components of the adaptive immune response?
T lymphocytes
CD4 T cells
CD8 T cells
B lymphocytes
B cells
Plasma cells
Antibodies
Soluble components
Cytokines and chemokines
What is the definition of a primary lymphoid organ?
Organs involved in lymphocyte development
What does the bone marrow do?
Both T and B lymphocytes are derived from haematopoetic stem cells
Site of B cell maturation
What does the thymus do?
Site of T cell maturation.
Most active in the foetal and neonatal period, involutes after puberty
How do lymphoid cells develop?
T:
Pre T -> Thymic selection -> CD4/CD8
B:
Pro B -> Pre B -> IgM B cells -> Memory cells or Plasma cells
What is reticular dysgenesis?
- most severe form of severe combined immunodeficiency (SCID)
- mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2)
What does reticular dysgenesis cause?
Failure of production of: Lymphocytes Neutrophils Monocyte/macrophages Platelets Fatal in very early life unless corrected with bone marrow transplantation
What stops lymphoid progenitors from differentiating?
Other forms of severe combined
immunodeficiency (SCID)
What are the causes of SCID?
> 20 possible pathways identified
Deficiency of cytokine receptors
Deficiency of signalling molecules
Metabolic defects
Effect on different lymphocyte subsets (T, B, NK) depend on exact mutation
What is X linked SCID?
45% of all severe combined immunodeficiency
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells
Mutation of common gamma chain on chromosome Xq13.1
Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21
Phenotype
Very low or absent T cell numbers (Arrested development)
Normal or increased B cell numbers but low Igs (High immature B cells)
Very low or absent NK cell numbers (Arrested Development)
What is ADA deficiency?
16.5% of all severe combined immunodeficiency
Adenosine Deaminase Deficiency
Enzyme lymphocytes required for cell metabolism
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 B cell numbers
Very low or absent NK cell numbers
What is the clinical phenotype of SCID?
Unwell by 3 months of age - before are protected by mother’s IgG
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
What protects the SCID neonate in the first 3 months of life?
Source of circulating IgG from placenta and colostrum
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
Which T cells recognise which HLA receptors?
CD8+ T cells recognise peptide presented by HLA class I molecules CD4+ T cells recognise peptide presented by HLA class II molecules
How does central tolerance work for T cells?
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 does selection work for T cells?
Negative selection
to avoid autoreactivity - Differentiate as
CD8+ T cell
Intermediate affinity for
HLA class II - Differentiate as
CD4+ T cell
What are 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 T helpers do?
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 do Th1, Th17, Treg, TFh and Th2 do?
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
What is DiGeorge syndrome?
Deletion at 22q11.2
TBX1 may be responsible for some features
Usually sporadic rather than inherited
Developmental defect of pharyngeal pouch- ABNORMAL THYMUS
What are the signs and symptoms of DiGeorge’s?
High forehead
Low set, abnormally folded ears
cleft palate, small mouth and jaw
Hypocalcaemia
Oesophageal atresia
Underdeveloped thymus
Complex congenital heart disease
Normal numbers B cells Reduced numbers T cells Homeostatic proliferation with age Immune function usually only mildly impaired and improves with age
What does MHC II deficiency cause?
Lack of active selection of cells that recognise peptides in conjunction with MHC Class II
What is Bare lymphocyte syndrome – type 2?
Absent expression of MHC Class II molecules
Defect in one of the regulatory proteins involved in Class II gene expression, Regulatory factor X, Class II transactivator
Phenotype:
Low/ normal T cells (V low CD4, normal CD8)
Normal B cells (Low IgG/IgA due to los CD4Th)
(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 the disorders of T cell effector function?
Cytokine production – IFN
Cytokine receptors – IL12 receptor
Cytotoxicity
T-B cell communication
What are the clinical features of T cell deficiencies?
Viral infections
Cytomegalovirus
Fungal infection
Pneumocystis, Cryptosporidium
Some bacterial infections – esp intracellular organisms; Mycobacteria tuberculosis, Salmonella
Early malignancy
What investigations would you use for T cell deficiencies?
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
FACS
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 does central tolerance work for B cells?
No recognition of self
in bone marrow - Survive
Recognition of self
In bone marrow - Negative selection
to avoid autoreactivity
What happens when B cells encounter an antigen initially?
Early IgM response – T cell independent
Incl.s:
IgM memory cell and
Ab secreting plasma cell
What is the germinal centre reaction?
After initial Early IgM response of B cells (now T cell dependent)
- Dendritic cells prime CD4+ T cells
- CD4+ T cell help for B cell differentiation Requires CD40L:CD40
- B cell proliferation- Somatic hypermutation, Isotype switching to IgG, A , E
High affinity memory cells and plasma cells appear
What are immunoglobulins?
Soluble proteins made up of two heavy and two light chains
What are the classes of Ig?
IgM, IgG, IgA, IgE, IgD,
subclasses of IgG and IgA also occur.
What is the structure of Ig?
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 hypogammaglobulinaemia?
It is characterized by the absence of mature B cells which in turn leads to severe antibody deficiency and recurrent infections.
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 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 are the Genetic mutations in 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 is 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?
Low IgG, IgA and IgE
Recurrent bacterial infections
Cause unknown
What is common variable immune deficiency defined by?
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
What are the Clinical features in adults and children in Common variable immune deficiency?
Clinical features – 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
What is selective IgA deficiency like?
Prevalence = 1:600
2/3rd individuals asymptomatic
1/3rd have recurrent respiratory tract infections
Genetic component, but cause as yet unknown
What are the clinical features of lymphocyte deficiencies?
Bacterial infections
Staphylococcus, Streptococcus
Toxins
Tetanus, Diptheria
Some viral infections
Enterovirus
What Investigations would you do in 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.
What is the management of B cell immunodeficiency?
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
Which condition is described by:
Severe recurrent infections from
3 months,CD4 and CD8 T cells absent, B cell present, Igs low.
Normal facial features and cardiac echocardiogram
X linked SCID
Which condition is described by: Young adult with chronic
infection with Mycobacterium marinum
IFN gamma receptor deficiency
What is condition is described by:
Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
22q 11.2 deletion syndrome (Di George’s)
Which condition is described by: 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 II
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
Common variable immunodeficiency
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
X linked hyper IgM syndrome due to CD40ligand 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
What are the lab tests for PID?
White cells Full blood count Lymphocyte subsets Special tests for white cell migration/function - Adhesion molecules – eg CD18 - Test for oxidative killing – DHR test Immunoglobulins IgM, IgG, IgA Specific Igs and response to vaccination Complement Complement function - CH50 and AP50 Individual complement components
