Immuno 2 - The immune response to infection/Primary immune deficiencies Part 2 Flashcards

1
Q

B cells emerge from the bone marrow as Ig_?__ expressing B cells

A

IgM

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2
Q

Reticular dysgenesis mutation

A

mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

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3
Q

Which features would make you suspicious of SCID

A
Unwell by 3 months of age*
Infections of all types
Failure to thrive
Persistent diarrhoea
o	Unusual skin disease
	Colonisation of infant’s empty BM by maternal lymphocytes  graft vs host disease

FHx of early infant death

*(before – protected by IgG from mother across placenta and then colostrum)
• Normal baby will start to produce their own IgG over the course of 6 months

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4
Q

X-linked SCID mutation

A

Mutation of common γ chain of IL2 on Chr Xq13.1

shared by cytokine receptors IL-
2
7
9
15
21
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5
Q

X-linked SCID

T cells
NK cells
B cells
IgG

A

o Cells mature but are unable to respond to cytokines

early arrest of T cell + NK cell development
production of immature B cells

  • Very low/absent T cells
  • Very low/absent NK cells
  • Normal or increased B cells (but don’t function well)
  • Low IgG
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6
Q

ADA deficiency

T cells
NK cells
B cells

A

Adenosine Deaminase deficiency

inability to respond to cytokines

  • Very low/absent T cells
  • Very low/absent NK cells
  • Very low/absent B cells
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7
Q

What do CD8 cells vs CD4 cells recognise

A

CD8
o Peptides derived from intracellular proteins in association with HLA class I (HLA-A, HLA-B, HLA-C)
o Malignant or virus infected cells

CD4
o	Peptides derived from extracellular proteins presented on HLA class II molecules (HLA-DR, HLA-DP, HLA-DQ)
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8
Q

Function of
• Treg
• T follicular helper cells (Tfh)

cells

A
  • Treg – important in negatively regulating immune responses, keeping them under control
  • T follicular helper cells (Tfh) – important in the development of B cell responses– play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells
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9
Q

DiGeorge syndrome features

characteristics
T cells
B cells
Immune function

A

Defects in T cell maturation/selection in thymus

CATCH22
o Complex congenital heart disease (esp. tetralogy of fallot)
o Abnormal facies (high forehead, low set ears, abnormally folded ear, cleft palate, small mouth, small jaw, oesophageal atresia)
o Thymic aplasia (T cell lymphopenia)
o Cleft palate
o Hypocalcaemia, Hypoparathyroidism
o 22 – chromosome - deletion at 22q11.2

o Reduced T cells
 Over time T cells proliferate to fill up the compartment and so their immune function tends to improve with age

o Normal B cells
 Low IgA, Low IgG (no T follicular helper cells to help differentiation to IgG or IgA producing B cells in germinal centre reaction)
o Homeostatic proliferation with age

 Immune function usually only mildly impaired + improves with age

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10
Q

Bare lymphocyte syndrome

where is the problem
T cells
B cells
IgG
IgA
A

Defects in T cell maturation/selection in thymus

• Defect in one of the regulatory proteins involved in Class II gene expression
o Regulatory factor X
o Class II transactivator

• Absent expression of MHC Class II molecules  Profound deficiency of CD4+ cells

o Normal numbers of CD8+
o Low numbers of CD4+ (profound deficiency of CD4+ cells)
o Normal numbers of B cells
o Low IgG or IgA antibodies (lack of CD4+ T cell help, no class switching)

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11
Q

Syndromes due to Defects in T cell maturation/selection in thymus

A

DiGeorge syndrome - 22q11.2 deletion

Bare lymphocyte syndrome type 2

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12
Q

Causes of disordered T activation/ cell effector function

A

Failure of
• Cytokine production – IFN
• Cytokine receptors – IL12 receptor
• T-B cell communication

• Cytotoxicity

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13
Q

Clinical features of T cell deficiency

A

• T cell deficiency clinical features
o Viral infections – CMV
o Fungal infection – pneumocystis, cryptosporidium
o Some bacterial infections, esp. intracellular organisms – TB, Salmonella
o Early malignancy

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14
Q

T cell deficiencies ix

A

• Total WCC + differential
o Remember that lymphocyte counts are normally much higher in children than in adults

• Lymphocyte subsets
o Quantify CD8 T cells, CD4 T cells, B cells, NK cells

• Immunoglobulins
o If CD4 T cell deficient (because if there is CD4 T cell deficiency, you wont be able to generate your immunoglobulins in the germinal centre reaction)

• Functional tests of T cell activation + proliferation
o Useful if signalling or activation defects are suspected

• HIV test

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15
Q

Management of immunodeficiency involving T cells

A
  • Aggressive prophylaxis/ treatment of infection
  • Ig replacement

• Enzyme replacement therapy
o PEG-ADA for ADA SCID

• HSCT
o To replace abnormal populations in SCID
o To replace abnormal cells – class II deficient APCs in BLS

• Thymic transplantation
o To promote T cell differentiation in Di George syndrome
o Cultured donor thymic tissue transplanted in quadriceps muscle

• Gene therapy
o Stem cells treated ex-vivo with viral vectors containing missing components
o Transduced cells have survival advantage in vivo

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16
Q

What are Th1 cells?

A

Subset of lymphocytes
express CD4
secrete IL-2, IFNγ
Help CD8 cells + macrophages

17
Q

Describe what happens before and during the germinal centre reaction

A

o Dendritic cells prime the CD4+ T cells in the lymph nodes

Take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules.

o CD4+ T cells help B cell differentiation – requires CD40L:CD40 interaction

• CD4+ cells interact w B cells germinal centres (found in secondary lymphoid organs)

in the germinal centre reaction, the B cells undergo
o Somatic hypermutation  they edit their receptor on successive ranks of antigen engagement until it becomes very high affinity = stronger and more specific response to the antigen = affinity maturation
o Isotype switching from IgM to IgG, IgA or IgE
o B cell proliferation

18
Q

Immunoglobulins

What determines the antibody class
Antigen is recognised by...
Effector function is determined by...
IgA is a 
IgM is a 
IgE, IgD, IGg are
A

What determines the antibody class - Heavy chain

Antigen is recognised by antigen binding regions (Fab) on both heavy + light chains
• Antibodies identify pathogens and toxins (Fab mediated)

Effector function is determined by constant region on the heavy chain (Fc)
• Interact with other components of immune response to remove pathogens (Fc mediated)
o Fc binds to Complement, Phagocytes, NK cells to help remove antigens and toxins

IgA is a dimer
IgM is a pentamer
IgE, IgD, IgG are monomers

19
Q

Response to successive exposures to antigen is dominated by

A

IgG

20
Q

Bruton’s x-linked hypogammaglobulinemia/ agammaglobulinemia

What is wrong
When does it present
How does it present

A
  • Abnormal BTK (B cell tyrosine kinase) gene – mutation in B cell tyrosine kinase
  • Pre-B cells cannot develop into mature B cell  Absence of mature B cells  no antibody production

• No circulating IgG 3 months after birth (agammaglobulinemia - not even IgM)
o Boys (X-linked!) present in first few years of life
o Recurrent bacterial infections – otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis
o Viral, fungal, parasitic infections – enterovirus, pneumocystis
o Absent/scanty lymph nodes and tonsils (1o follicles and germinal centres absent)
o Failure to thrive

21
Q

X-linked hyper IgM syndrome

Where is the problem
Mode of inheritance
What does this problem cause

Clinical phenotype

Features
o	Number of circulating B cells
o	Number of T cells 
o	serum IgM
o	serum IgA, IgE, IgG
A

o Mutation in CD40 ligand gene (CD40L, CD154) (encoded in Xq26)
• X-linked recessive

  • Inability of B cells to class switch causing production of only IgM
  • Lack of isotype switch due to a failure of T cell co-stimulation

• B cell maturation defect
o IgM B cells cannot develop into IgM memory and plasma cells
o IgM B cells can’t undergo a germinal centre reaction

• Clinical phenotype
o Boys (X linked!) present in first few years of life
o Recurrent infections – bacterial
o Subtle abnormality in T cell function – predisposition to pneumocystis jiroveci infection, autoimmune disease and malignancy
o Failure to thrive

• Features
o Normal number of circulating B cells
o Normal number of T cells but activated cells do not express CD40L
o No germinal centre development within lymph nodes + spleen
 Failure of isotype switching
• Elevated serum IgM
• Undetectable IgA, IgE, IgG

22
Q

Common variable immune deficiency

Features
o Number of B cells
o serum IgM
o serum IgA, IgE, IgG

Where is the problem

Definition

A

o Number of B cells - normal
o serum IgM - normal
o serum IgA, IgE, IgG - low

o Failure of normal B cell maturation –> Reduction in immunoglobulins
o Mutation in MHC III

Defined by
o Marked reduction in IgG, with low IgA or IgM
o Poor/absent response to immunisation/vaccination
o Frequent infections
o Absence of other defined immunodeficiency

Associated with NHL, autoimmune diseases

23
Q

Common variable immune deficiency

Clinical features

A

• Clinical features – adults and children

o Recurrent bacterial infections
 Pneumonia, persistent sinusitis, gastroenteritis
 Often with severe end-organ damage

o	Pulmonary disease
	Interstitial lung disease
	Granulomatous interstitial lung disease (also LN, spleen)
	Obstructive airways disease
	Bronchiectasis 

o GI disease
 Inflammatory bowel like disease
 Sprue like illness
 Bacterial overgrowth

o	Autoimmune disease 
	Autoimmune haemolytic anaemia or thrombocytopenia
	Rheumatoid arthritis
	Pernicious anaemia
	Thyroiditis
	Vitiligo 

o Malignancy
 NHL

24
Q

Selective IgA deficiency

What percentage of people are symptomatic

what kind of infections do they suffer from

A
  • 2/3 individuals asymptomatic
  • 1/3 have recurrent respiratory tract infections
  • Also GI infections
25
Q

Failure of B cell maturation
Failure of T cell costimulation
Failure of IgA production
Failure of production of IgG antibodies

A

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

26
Q

Investigation of B cell deficiencies

A

• Total WCC + differentials – do they have lymphocytes?

• Lymphocyte subsets
o B cells, CD4, CD8 T cells, NK cells

• Serum immunoglobulins and protein electrophoresis
o IgG production is dependent on both the B cells and the CD4 T cells  Production of IgG is surrogate maker of CD4 T cell helper function
o Therefore serum IgG if CD4 deficient

• Functional tests of B cell function
o Specific antibody responses to known pathogens/immunisations – measure IgG antibodies against tetanus, Haemophilus influenzae B, Strep. Pneumoniae
o If specific antibody levels are low, immunise with appropriate killed vaccine and repeat antibody measurement 6-8 weeks later to see if they have responded

• HIV

27
Q

Protein electrophoresis for investigation of B cell deficiencies

which band gives you the antibodies?

findings in
Bruton’s X-linked hypogammaglobulinaemia

Monoclonal gammopathy (abnormal production of a single clone of plasma cells/antibodies)

A

On protein electrophoresis, it’s the γ band that gives you the antibodies – it’s all the antibodies, not just IgG

e.g. Brutons  absent γ band

monoclonal gammopathy (abnormal production of a single clone of plasma cells/antibodies)  high narrow peak in the γ band

28
Q
CD4 
CD8
Bcell
IgM
IgG
IgA in
SCID
Bruton's X-linked
HyperIgM X-linked
Selective IgA
CIVD
A

Look at table - ix of B cell deficiencies

29
Q

Management of immunodeficiency involving B cells

A

• Aggressive prophylaxis/treatment of infection

• Immunoglobulin replacement if required
o Derived from pooled plasma from thousands of donors
o Contains IgG antibodies to a wide variety of common organisms
o Aim of maintaining trough IgG levels within normal range
o Treatment is lifelong, every 3 weeks

• Immunisation
o For selective IgA deficiency (because it will boost the other responses)
o Not otherwise effective because of defect in IgG antibody production

• (for B cell immunodeficiencies you don’t usually do transplantations because what you are missing is the immunoglobulins and you can replace these)

30
Q

Primary lymphoid organs

Secondary lymphoid organs

A

Primary lymphoid organs
• Sites of B and T cell development
• BM - B + T cell production, B cell maturation
• Thymus - T cell maturation

Secondary lymphoid organs
•	Anatomical sites of interaction between naïve lymphocytes and microorganisms
•	Spleen
•	Lymph nodes
•	Mucosal associated lymphoid tissue
31
Q

Summary

Pre-B cells 
IgA 
IgG secreting plasma cells 
IgM secreting plasma cells 
Primary lymphoid organs 
Thoracic duct
Thymus 
Germinal centre
A

Pre-B cells – exist within the bone marrow and develop from haematopoietic stem cells
IgA – divalent antibody present within mucous which helps provide a constitutive barrier to infection
IgG secreting plasma cells – cell dependent on the presence of CD4 T cell help for generation
IgM secreting plasma cells – are generated rapidly following antigen recognition and are not dependent on CD4 T cell help
Primary lymphoid organs – include both the bone marrow and the thymus; sites of B and T cell development
Thoracic duct – carries lymphocytes from lymph nodes back to the blood circulation
Thymus – site of deletion of T cells with inappropriately high or low affinity for HLA molecules and of maturation of T cells into CD4+ or CD8+ cells
Germinal centre – area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotype switching

32
Q

Types of primary immunodeficiency affecting

Phagocytes

Natural Killer cells

Complement

A

Phagocytes
Kostmann syndrome
Leukocyte adhesion deficiency
Chronic granulomatous disease

Natural Killer cells
Classical NK deficiency
Functional NK deficiency

Complement
Classical pathway deficiencies
Alternative pathway deficiencies
Terminal pathway deficiencies

33
Q

Types of primary immunodeficiency affecting

Haematopoietic stem
cells

Cytokines

Lymphoid precursors

A

Haematopoietic stem
cells
Reticular dysgenesis

Cytokines
IL12 and IL12 receptor deficiency
IFNg and IFNg receptor deficiency

Lymphoid precursors
Severe combined immunodeficiency

34
Q

Types of primary immunodeficiency affecting

T cells

B cells

A

T cells
22q11.2 deletion syndromes
Bare lymphocyte syndrome

B cells
X-linked agammaglobulinaemia
X-linked hyperIgM syndrome 
Common variable immunodeficiency
IgA deficiency
35
Q

Laboratory Tests for Primary Immunodeficiency

White cells
Immunoglobulins
Complement

A
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 component

36
Q

What kind of conditions are seen in T cell deficiency

A

Intracellular + maligancy

Viral infections (CMV)

Fungal infection (Pneumocystis, Cryptosporidium)

Some bacterial infections (esp. intracellular TB, Salmonella)

Early malignancy

37
Q

What kind of conditions are seen in B cell deficiency

A

Bacterial infections (Staph, Strep)

Toxins (Tetanus, Diptheria)

Some viral infections (enterovirus)