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Kat's Pathology > Primary Immune Deficiencies 2 > Flashcards

Primary Immune Deficiencies 2 Flashcards

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1
Q

What IG is the first to be produced

A

IgM

IgG, E and A are produced thereafter

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2
Q

What is reticular dysgenesis

A

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

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3
Q

Causes of severe combined immunodeficiency

A

> 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

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4
Q

What is X-linked SCID

A

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.

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5
Q

Phenotypes of X-linked SCIDs

A

Very low or absent T cell numbers
Very low of absent NK cell numbers
Normal or increased B cell numbers but low Igs.

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6
Q

Adenosine Deaminase Deficiency (ADA)

A

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

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7
Q

ADA deficiency phenotype

A

Very low or absent T cell numbers
Very or absent B cell numbers
Very low of absent NK cell numbers

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8
Q

Clinical presentation of SCIDs

A

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

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9
Q

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

A

Active transport of maternal IgG across placenta before birth
IgG in colostrum

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10
Q

T lymphocyte maturation

A

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

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11
Q

How do T cell receptors recognise HLA/peptide complexes

A 
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
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12
Q

T cells with low affinity for HLA

A

Not selected to avoid inadequate reactivity

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13
Q

T cells with intermediate affinity for HLA

A

Positive selection - approximately 10% of original cells

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14
Q

T cells with high affinity for HLA

A

Negative selection to avoid autoreactivity

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15
Q

Intermediate affinity for HLA class 1

A

Differentiate as CD8+ T cells

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16
Q

Intermediate affinity for HLA class 2

A

Differentiate as CD4+ T cells

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17
Q

Features of CD8+ 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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18
Q

What do CD8+ cytotoxic T cells protect against

A

Particularly important in defence against viral infections and tumours

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19
Q

What do CD8+ cytotoxic T cells secrete

A

IFNg

TNFa

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20
Q

Functions of CD4+ helper T cells

A 
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

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21
Q

Function of Th1 CD4+ T cells

A

Help CD8 T cells and macrophages

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22
Q

What do Th1 CD4+ T cells secrete

A

IL2
INFg
TNFa
IL10

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23
Q

Function of CD4+ Th17 T cells

A

Help neutrophil recruitment

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24
Q

What do CD4+ Th17 T cells secrete

A

IL17
IL21
IL22

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25
What do Treg CD4+ T cells secrete
IL10 Foxp3 CD25
26
Function of Treg CD4+ T cells
IL10/TGF beta expressing CD25+Foxp3+
27
Function of TFh CD4+ T cells
Follicular helper T cells
28
What do TFh CD4+ T cells secrete
IL2 IL10 IL21
29
Function of Th2 CD4+ T cells
Helper T cells
30
What do Th2 CD4+ T cells secrete
IL4 IL5 IL13 IL10
31
Where are T cells primed
Thymus gland
32
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
33
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
34
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 ```
35
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
36
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
37
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
38
Disorders of T cell effector function
Cytokine production - IFN Cytokine receptors - IL12R Cytotoxicity
39
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.
40
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
41
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
42
``` 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
43
X-linked SCID
``` Low CD4 T cells Low CD8 T cells Low NK cells Normal or low IgM Low IgG ```
44
``` Low CD4 T cells Low CD8 T cells Normal NK cells Normal B cells Normal or low IgG ```
DiGeorge syndrome
45
DiGeorge syndrome
``` Low CD4 T cells Low CD8 T cells Normal NK cells Normal B cells Normal IgM Normal or low IgG ```
46
``` Low CD4 T cell Normal CD8 T cell Normal NK cells Normal B cells Normal IgM Low IgG ```
BLS type 2
47
BLS type 2
``` Low CD4 T cell Normal CD8 T cell Normal NK cells Normal B cells Normal IgM Low IgG ```
48
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.
49
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
50
Young adult with chronic infection with Mycobacterium marinum
IFNg receptor deficiency
51
Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG
DiGeorge syndrome
52
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
53
B cells with no recognition of self in bone marrow
Survive
54
B cells with recognition of self in bone marrow
Negative selection to avoid autoreactivity
55
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.
56
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)
57
Single chain Igs
IgG IgD IgE
58
Dimeric Igs
IgA
59
Pentameric Ig
IgM
60
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
61
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
62
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
63
B cell maturation defect
Hyper IgM syndrome
64
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.
65
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
66
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
67
Common variable immune deficiency
Low IgG, IgA and IgE Recurrent bacterial infections Cause unknown
68
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
69
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
70
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%
71
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
72
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
73
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.
74
``` Normal CD4 T cells Normal CD8 T cells Low B cells Low IgM Low IgG Low IgA ```
Bruton's X-linked
75
Bruton's X-linked
``` Normal CD4 T cells Normal CD8 T cells Low B cells Low IgM Low IgG Low IgA ```
76
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Raised IgM Low IgG Low IgA ```
Hyper IgM X-linked
77
Hyper IgM X-linked
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Raised IgM Low IgG Low IgA ```
78
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Normal IgG Low IgA ```
Selective IgA deficiency
79
Selective IgA deficiency
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Normal IgG Low IgA ```
80
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Low IgG Normal or low IgA ```
CVID
81
CVID
``` Normal CD4 T cells Normal CD8 T cells Normal B cells Normal IgM Low IgG Normal or low IgA ```
82
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
83
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE
Common variable immunodeficiency
84
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
85
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
86
Recurrent respiratory tract infections, absent IgA, normal IgM and IgG
IgA deficiency
87
Phagocyte immunodeficiencies
Kostmann syndrome Leukocyte adhesion deficiency Chronic granulomatous disease
88
Natural killer cells immunodeficiency
Classical NK deficiency | Functional NK deficiency
89
Complement immunodeficiencies
``` Classical pathway deficiencies MBL deficiency Alternative pathway deficiencies C3 deficiency Terminal pathway deficiencies ```
90
Cytokine immunodeficiencies
IL12 and IL12 receptor deficiency | IFNg and IFNg receptor deficiency
91
Haematopoietic stem cells immunodeficiencies
Reticular dysgenesis
92
Lymphoid precursors immunodeficiencies
Severe combined immunodeficiency
93
T cell immunodeficiencies
22q11.2 deletion syndromes | Bare lymphocyte syndrome
94
B cell immunodeficiencies
Bruton X-linked agammaglobulinaemia X-linked hyperIgM syndrome Common variable immunodeficiency IgA deficiency

Kat's Pathology (105 decks)

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