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Primary Immune deficiency 2 Flashcards

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1
Q

What are the components of the adaptive immune response?

A

T lymphocytes
CD4 T cells
CD8 T cells

B lymphocytes
B cells
Plasma cells
Antibodies

Soluble components
Cytokines and chemokines

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2
Q

What is the definition of a primary lymphoid organ?

A

Organs involved in lymphocyte development

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3
Q

What does the bone marrow do?

A

Both T and B lymphocytes are derived from haematopoetic stem cells
Site of B cell maturation

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4
Q

What does the thymus do?

A

Site of T cell maturation.

Most active in the foetal and neonatal period, involutes after puberty

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5
Q

How do lymphoid cells develop?

A

T:
Pre T -> Thymic selection -> CD4/CD8

B:
Pro B -> Pre B -> IgM B cells -> Memory cells or Plasma cells

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6
Q

What is reticular dysgenesis?

A
  • most severe form of severe combined immunodeficiency (SCID)
  • mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2)
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7
Q

What does reticular dysgenesis cause?

A 
Failure of production of:
Lymphocytes
Neutrophils
Monocyte/macrophages 
Platelets
Fatal in very early life unless corrected with bone marrow transplantation
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8
Q

What stops lymphoid progenitors from differentiating?

A

Other forms of severe combined

immunodeficiency (SCID)

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9
Q

What are the causes of SCID?

A

> 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

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10
Q

What is X linked SCID?

A

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)

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11
Q

What is ADA deficiency?

A

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

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12
Q

What is the clinical phenotype of SCID?

A

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

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13
Q

What protects the SCID neonate in the first 3 months of life?

A

Source of circulating IgG from placenta and colostrum

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14
Q

How do T cells mature?

A

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

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15
Q

Which T cells recognise which HLA receptors?

A 
CD8+ T cells recognise peptide presented by HLA class I molecules
CD4+ T cells recognise peptide presented by HLA class II molecules
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16
Q

How does central tolerance work for T cells?

A

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

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17
Q

How does selection work for T cells?

A

Negative selection
to avoid autoreactivity - Differentiate as
CD8+ T cell

Intermediate affinity for
HLA class II - Differentiate as
CD4+ T cell

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18
Q

What are Cytotoxic T cells?

A

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

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19
Q

What do T helpers do?

A

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

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20
Q

What do Th1, Th17, Treg, TFh and Th2 do?

A

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

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21
Q

What is DiGeorge syndrome?

A

Deletion at 22q11.2
TBX1 may be responsible for some features
Usually sporadic rather than inherited
Developmental defect of pharyngeal pouch- ABNORMAL THYMUS

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22
Q

What are the signs and symptoms of DiGeorge’s?

A

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
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23
Q

What does MHC II deficiency cause?

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A

Lack of active selection of cells that recognise peptides in conjunction with MHC Class II

24
Q

What is Bare lymphocyte syndrome – type 2?

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A

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)

25
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
26
What are the disorders of T cell effector function?
Cytokine production – IFN Cytokine receptors – IL12 receptor Cytotoxicity T-B cell communication
27
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
28
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
29
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
30
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
31
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
32
What is the germinal centre reaction?
After initial Early IgM response of B cells (now T cell dependent) 1. Dendritic cells prime CD4+ T cells 2. CD4+ T cell help for B cell differentiation Requires CD40L:CD40 3. B cell proliferation- Somatic hypermutation, Isotype switching to IgG, A , E High affinity memory cells and plasma cells appear
33
What are immunoglobulins?
Soluble proteins made up of two heavy and two light chains
34
What are the classes of Ig?
IgM, IgG, IgA, IgE, IgD, | subclasses of IgG and IgA also occur.
35
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)
36
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
37
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
38
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 ```
39
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 ```
40
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
41
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
42
What is common variable immune deficiency?
Low IgG, IgA and IgE Recurrent bacterial infections Cause unknown
43
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
44
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
45
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
46
What are the clinical features of lymphocyte deficiencies?
Bacterial infections Staphylococcus, Streptococcus Toxins Tetanus, Diptheria Some viral infections Enterovirus
47
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.
48
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
49
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
50
Which condition is described by: Young adult with chronic | infection with Mycobacterium marinum
IFN gamma receptor deficiency
51
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)
52
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
53
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
Common variable immunodeficiency
54
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
X linked hyper IgM syndrome due to CD40ligand mutation
55
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
56
Recurrent respiratory tract infections, absent IgA, normal IgM and IgG
IgA deficiency
57
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 ```

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