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Kat's Pathology > Primary Immune Deficiencies 2 > Flashcards

Primary Immune Deficiencies 2 Flashcards

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
Q

What do Treg CD4+ T cells secrete

A

IL10
Foxp3
CD25

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26
Q

Function of Treg CD4+ T cells

A

IL10/TGF beta expressing CD25+Foxp3+

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27
Q

Function of TFh CD4+ T cells

A

Follicular helper T cells

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28
Q

What do TFh CD4+ T cells secrete

A

IL2
IL10
IL21

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29
Q

Function of Th2 CD4+ T cells

A

Helper T cells

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30
Q

What do Th2 CD4+ T cells secrete

A

IL4
IL5
IL13
IL10

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31
Q

Where are T cells primed

A

Thymus gland

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32
Q

Where are T cells produced

A

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

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33
Q

What is DiGeorge syndrome

A

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

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34
Q

Clinical features of DiGeorge syndrome

A 
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
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35
Q

What is involved in MCH class 2 selective CD4+ T lymphocyte development

A

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

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36
Q

What is bare lymphocyte syndrome - type 2

A

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

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37
Q

Clinical phenotype presentation of BLS

A

Unwell by 3 months of age
Infections of all types: bacterial, viral, fungal, protozoal
Failure to thrive
Family history of early infant death

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38
Q

Disorders of T cell effector function

A

Cytokine production - IFN
Cytokine receptors - IL12R
Cytotoxicity

39
Q

Summary of types of T cell defects

A

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
Q

Clinical features of T lymphocyte deficiency

A

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
Q

Investigations for T cell deficiencies

A

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
Q 
Low CD4 T cells 
Low CD8 T cells 
Low NK cells
Normal or low B cells 
Normal or low IgM
Low IgG
A

X linked SCID

43
Q

X-linked SCID

A 
Low CD4 T cells 
Low CD8 T cells
Low NK cells  
Normal or low IgM
Low IgG
44
Q 
Low CD4 T cells 
Low CD8 T cells 
Normal NK cells 
Normal B cells 
Normal or low IgG
A

DiGeorge syndrome

45
Q

DiGeorge syndrome

A 
Low CD4 T cells 
Low CD8 T cells 
Normal NK cells 
Normal B cells 
Normal IgM
Normal or low IgG
46
Q 
Low CD4 T cell 
Normal CD8 T cell 
Normal NK cells 
Normal B cells 
Normal IgM 
Low IgG
A

BLS type 2

47
Q

BLS type 2

A 
Low CD4 T cell 
Normal CD8 T cell 
Normal NK cells 
Normal B cells 
Normal IgM 
Low IgG
48
Q

Management of immunodeficiency involving T cells

A

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
Q

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

A

X-linked SCID

50
Q

Young adult with chronic infection with Mycobacterium marinum

A

IFNg receptor deficiency

51
Q

Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, low IgA and IgG

A

DiGeorge syndrome

52
Q

6 month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG low

A

Bare lymphocyte syndrome type 2

53
Q

B cells with no recognition of self in bone marrow

A

Survive

54
Q

B cells with recognition of self in bone marrow

A

Negative selection to avoid autoreactivity

55
Q

B cell response to antigen encounter

A

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
Q

What are immunoglobulins

A

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
Q

Single chain Igs

A

IgG
IgD
IgE

58
Q

Dimeric Igs

A

IgA

59
Q

Pentameric Ig

A

IgM

60
Q

Function of antibodies

A

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
Q

Bruton’s X-linked hypogammaglobulinaemia

A

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
Q

Clinical presentation of Bruton’s X-linked a-gammaglobulinaemia

A

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
Q

B cell maturation defect

A

Hyper IgM syndrome

64
Q

Hyper IgM syndrome

A

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
Q

Features of hyper IgM syndrome - CD40L deficiency

A

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
Q

Clinical presentation of X-linked hyper IgM

A

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
Q

Common variable immune deficiency

A

Low IgG, IgA and IgE
Recurrent bacterial infections
Cause unknown

68
Q

Features of common variable immune deficiency

A

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
Q

Clinical features of common variable immune deficiency in adults and children

A

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
Q

Selective IgA deficiency

A

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
Q

Summary of B cell maturation defects

A

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
Q

Clinical features of lymphocyte deficiencies

A

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
Q

Investigations of B cell deficiencies

A

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
Q 
Normal CD4 T cells
Normal CD8 T cells 
Low B cells 
Low IgM 
Low IgG
Low IgA
A

Bruton’s X-linked

75
Q

Bruton’s X-linked

A 
Normal CD4 T cells
Normal CD8 T cells 
Low B cells 
Low IgM 
Low IgG
Low IgA
76
Q 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Raised IgM
Low IgG
Low IgA
A

Hyper IgM X-linked

77
Q

Hyper IgM X-linked

A 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Raised IgM
Low IgG
Low IgA
78
Q 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Normal IgM
Normal IgG
Low IgA
A

Selective IgA deficiency

79
Q

Selective IgA deficiency

A 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Normal IgM
Normal IgG
Low IgA
80
Q 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Normal IgM
Low IgG
Normal or low IgA
A

CVID

81
Q

CVID

A 
Normal CD4 T cells
Normal CD8 T cells 
Normal B cells 
Normal IgM
Low IgG
Normal or low IgA
82
Q

Management of immunodeficiency involving B cells

A

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
Q

Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE

A

Common variable immunodeficiency

84
Q

Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, high IgM, absent IgA and IgG

A

X-linked hyper IgM syndrome due to CD40L mutation

85
Q

1 year old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent

A

Bruton’s X-linked hypogammaglobulinaemia

86
Q

Recurrent respiratory tract infections, absent IgA, normal IgM and IgG

A

IgA deficiency

87
Q

Phagocyte immunodeficiencies

A

Kostmann syndrome
Leukocyte adhesion deficiency
Chronic granulomatous disease

88
Q

Natural killer cells immunodeficiency

A

Classical NK deficiency

Functional NK deficiency

89
Q

Complement immunodeficiencies

A 
Classical pathway deficiencies
MBL deficiency 
Alternative pathway deficiencies
C3 deficiency
Terminal pathway deficiencies
90
Q

Cytokine immunodeficiencies

A

IL12 and IL12 receptor deficiency

IFNg and IFNg receptor deficiency

91
Q

Haematopoietic stem cells immunodeficiencies

A

Reticular dysgenesis

92
Q

Lymphoid precursors immunodeficiencies

A

Severe combined immunodeficiency

93
Q

T cell immunodeficiencies

A

22q11.2 deletion syndromes

Bare lymphocyte syndrome

94
Q

B cell immunodeficiencies

A

Bruton X-linked agammaglobulinaemia
X-linked hyperIgM syndrome
Common variable immunodeficiency
IgA deficiency

Kat's Pathology (105 decks)

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