IMMUNO: Primary Immunodeficiency Flashcards

Question

Which infections are most commonly associated with NK cell deficiencies?

Answer 1

1. Intracellular virus infections e.g. HHV infections 2. HPV - including malignancy (HPV associated cancers)

Answer 2

1. Prophylactic antivirals e.g. acyclovir or gancyclovir 2. Cytokines such as IFN-alpha to stimulate NK cytotoxic function 3. HPSC transplantation if severe

Answer 3

1. leukocyte adhesion deficiency 2. CGD 3. Kostmann syndrome 4. IFN-gamma R deficiency 5. Classical NK cell deficiency

Answer 4

\>20 tighly regulated, linked proteins produced in the **liver**

Answer 5

1. Activated by formation of antibody-antigen immune complexes 2. Contact results in change in antibody shape, exposing the binding site for C1 3. C1 binds to the antibody site which causes activation of the vascade ## Footnote *Dependent upon activation of acquired immune response (antibody)*

Answer 6

C1, C2, C4 --\> C3 ---\> C5-C9 (final common pathway) --\> membrane attack complex

Answer 7

1. Activated by direct binding of MBL to microbial cell surface carbohydrates 2. This stimulates the classical pathway C2 and C4 (NOT C1) --\> C3 ---\> C5-9 ## Footnote *Not dependent on the acquired immune response*

Answer 8

1. Activated by bacterial cell wall components e.g. lipopoolysaccharise of **gram negative** bacteria, teichoic acid of **gram positive** bacteria. 2. Involves **factors B, D** and **properidin**. 3. **Factor H** is the control protein (usually -ve regulated to regulate spontaneous activation) ## Footnote *Not dependent on the acquired immune response.*

Answer 9

Triggers formation of the membrane attack complex via C5-9 ## Footnote *MAC causes membrane lesions*

Answer 10

1. Increases vascular permeability and cell trafficking to site of inflammation 2. Activates phagocytes 3. Opsonisation of pathogens to promote phagocytosis 4. Promotes clearance of immune complexes 5. Punches holes in bacterial membranes

Answer 11

Especially those by encapsulated bacteria: * Neisseria meningitides (esp in properidin and C5-9 deficiency) * Haemophilus influenzae * Streptococcus pneumoniae

Answer 12

Susceptibility to SLE because... * failure of phagocytosis --\> dead cells and nuclear debris * failure to clear immune complexes --\> immune complex deposition in blood vessels --\> small vessel vasculitis

Answer 13

Susceptibility to Neisseria meningitides

Answer 14

MBL2 mutations are common but NOT USUALLY ASSOCIATED WITH IMMUNODEFICIENCY

Answer 15

Persistent activation of the classical pathway leads to immune complex deposition and therefore low C3 and C4 NB: deficiency of C1q and C2 increases susceptibility to SLE

Answer 16

Nephritic factors = auto-antibodies against components of the complement pathway

Answer 17

Nephritic factors stabilise C3 convertases --\> C3 activation and consumption * Often associated with **glomerulonephritis** (classicaly membranoproliferative) * Also associated with **partial lipodystrophy** (fat lost from upper body)

Answer 18

1. SLE - leads to overconsumption of C3, C4 2. Nephritic factors - anti-C3 convertase so C3 overactivation leads to low C3 ## Footnote *NB: C3 and C4 are routinely measured in blood tests*

Answer 19

**CH50** - tests for C1, C2, C4, C3, C5-9 **AP50** - tests for C3, C5-9

Answer 20

* C1q deficiency leads to abnormal CH50 because classical pathway is not activated in the right way but normal AP50 because still activation alternate.* * Properidin is involved in the alternate pathway.* * C9 is part of classical and alternate as it is at the end.*

Answer 21

* Vaccination - pneumovax, meningovax, HIB vaccines especially * Prophylactic antibiotics * Treat infections aggressively * Screen family members

Answer 22

1 - 1 2 - 2 3 - 4

Answer 23

Primary lymphoid organ - organs involved in lymphocyte development **B cells** - develop and mature in BM **T cells** - develop in BM and mature in thymus

Answer 24

Reticular dysgenesis - mutation in the AK2 enzyme (adenylate kinase 2). HSC do not differentiate into myeloid/lymphoid lineages.

Answer 25

Fatal in early life unless corrcted with BM transplantation There is failure of production of lymphocytes, neutrophils, monocytes/macrophages, platelets.

Answer 26

*SCID because it is combined B and T cell deficiency.* X linked SCID - makes up 45% of all SCIDs

Answer 27

**Mutation of common gamma chain on chromosome Xq13.1** - if signalling in this chain is affected it affects downstream signalling via IL-2, IL-4, IL-7, IL-9, IL-15 and IL-2. Inability to respond to cytokines causes: 1. early arrest of T and NK cell development and production, 2. and immature B cells

Answer 28

Phenotype * Very low or absent T cell numbers * Very low or absent NK cell numbers * Normal or increased B cell numbers but l**ow Igs**

Answer 29

16. 5% of all SCID * **Adenosine Deaminase Deficiency** - enzyme required for cell metabolism in lymphocytes **Phenotype** * Very low or absent T cell numbers * Very low or absent B cell numbers * Very low or absent NK cell numbers

Answer 30

* Unwell by 3 months of age * Infections of all types * Failure to thrive * Persistent diarrhoea * Unusual skin disease - **colonisation of infant’s empty bone marrow** by maternal lymphocytes and **graft versus host disease** * Family history of early infant death

Answer 31

1. Only T cells which have intermediate affinity for HLA are positively selected (10%) - *those with low affinity for HLA are not selected, and high affinity are negatively selected to avoid autoreactivity.* 2. Those with intermediate affinity for HLA class I differentiate into CD8+, those with intermedate affinity for HLA class II differentiate into CD4+ cells

Answer 32

Cytotoxic cells 1. Recognise peptides derved from INTRACELLULAR proteins in association with HLA class I 2. Kill cells via perforin, granzymes and expression of Fas ligand 3. Secrete cytokines e.g. IFNgamma, TNFalpha *Defence against tumours and viral infections*

Answer 33

1. Recognise peptides derived from extracellular proteins presented on HLA class II molecules (HLA-DR, HLA-DP, HLA-DQ) 2. Provide help for development of full B cell responses 3. Povide help for development of some CD8+ T cell responses (2 and 3 are immunorregulatory functions via cell:cell or cytokine interactions)

Answer 34

Helper T cells

Answer 35

22q11.2 delection syndrome - TBX1 may be responsible for some features but most cases are **sporadic** rather than inherited Developmental defect of pharyngeal pouch

Answer 36

* High forehead * Low set, abnormally folded ears * Cleft palate * Hypocalcaemia * Oesophageal atresia * Underdeveloped thymus * Complex congenital heart disease **Normal B cell numbers** **Reduced number of T cells -** *homeostatic proliferation with age so immune function usually only mildly impaired and improves with age*

Answer 37

There is no formation of CD4+ T cells which recognise peptides from extracellular proteins in conjunction with MHC class II --\> **Bare lymphocyte syndrome type 2**

Answer 38

**_Regulatory factor X_** or **_Class II transactivator_** --\> absence of MHC II molecules _Phenotype:_ * Deficiency of CD4+ cells * Normal number of CD8+ cells * Low or normal IgG and IgA due to lack of CD4+ T cell help in germinal centres *BLS type 1 is where MHC I is absent.*

Answer 39

No CD4+ T cells which help with isotype switching to change IgM into IgA and IgG in the germinal centres

Answer 40

* Unwell by 3 months * Infections of all types * Failure to thrive * FH of early infant death

Answer 41

Defects in: * cytokine production - IFN * cytokine receptors - IL-12 * cytotoxicity * T-B cell communication (CD40 ligand deficiency)

Answer 42

* Viral infections e.g. CMV * Fungal infections e.g. pneumocytsic, cryptosporidium * Some bacterial infections esp intracellular organisms e.g. TB, salmonella * Early malignancy

Answer 43

* **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 * **Immunoglobulins** - if CD4 T cell deficient * **Functional tests of T cell activation and proliferation** - useful if signalling or activation defects are suspected * **HIV test**

Answer 44

T cells - CD8 and CD4 marker OR CD3 (both) B cells - CD20

Answer 45

* **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

Answer 46

1, 2 2, 4 3, 3 4, 1

Answer 47

IgM B cells

Answer 48

No recognition of seld in BM means that B cells survive and leave BM (those that recognise self are negatively selected to avoid autoreactivity) NB: NO INTERMEDIATES

Answer 49

1. _Early IgM response_ - T cell independent whereby IgM memory cells and Ab secreting plasma cells are found 2. _Germinal centre reaction in lymph node with CD4+ T cell help_ 1. Dendritic cells prime CD4+ cells 2. CD4+ cells help B cells differentate (via CD40L:CD40 interaction) 3. B cell proliferation, **somatic hypermutation**, i**sotype switching** to IgG, A, E --\> **high affinity memory cell and plasma cell production.**

Answer 50

2 heavy and 2 light chains 5 types - IgA, E, G, D, M (and subclasses of IgG and IgA) Antigen is recognised by **antigen binding region Fab (V)** Effector function determined by **constant region Fc (stem)**

Answer 51

Complement Phagocytes NK cells

Answer 52

Bruton's X-linked hypogammaglobulinaemia

Answer 53

Abnormal B cell tyrosine kinase (BTK) gene Absence of MATURE B cells and no IgG after 3 months (ONLY IN BOYS)

Answer 54

* Boys (present in first few years of life) * Recurrent bacterial infection - otitis media, sinusitis, pneumonia, osteomyelitis, septic arthritis, gastroenteritis * Viral, fungal, parasitis infections - enteroviruses, pneumocystis * Failure to thrive

Answer 55

Hyper IgM syndrome (X linked recessive)

Answer 56

**Mutation in CD40 ligand gene (CD40L, CD154) so that CD4+ T cells cannot offer help to B cells in germinal centres** Encoded on Xq26, member of TNF-R family DEFECT IS ON THE T CELL

Answer 57

Undetectable IgA, IgE and IgG Elevated serum IgM (no germinal centre development and no isotype switching)

Answer 58

In boys as with Bruton's Recurrent bacterial infections BUT abnormality in T cell also predisposes to PCP, AI disease and malignancy Failure to thrive

Answer 59

Defined by (1) **low IgA, IgG and IgE** (--\> recurrent bacterial infections,) (2) **poor response to immunisation**, (3) absence of o**ther immunodeficiency** COMMON and can present in childhood or adulthood with heterogenous genetic defects Due to failure of full differentation/function of B lymphocytes

Answer 60

Adults OR children affected **Recurrent bacterial infections** - pneumonia, persistent sinusitis, gastroenteritis, often with severe end-organ damage **Pulmonary disease** - interstitial lung disease, granulomatous interstitial lung disease (also LN, spleen), obstructive airways disease **Gastrointestinal disease** - IBD like disease, sprue like illness, bacterial overgrowth **Autoimmune disease** - AIHA or thrombocytopenia, RhA, pernicious anaemia, thyroiditis, vitiligo **Malignancy** - NHL

Answer 61

Prevalence high with 1:600 affected but only 1/3 are symptomatic (recurrent resp infections) Genetic component, cause yet unknown

Answer 62

Bacterial - staphylococcal, streptococcal Toxins - tetanus, diptheria Viral - enterovirus

Answer 63

* **Total WCC and differential** - lymphocyte counts in general are much higher in children than in adults * **Lymphocyte subset**s - to quantify B cells, CD4, CD8 and NK cells * **Serum Igs and protein electrophoresis** - production of IgG is a surrogate marker for CD4 T helper cell function * **Functinal tests of B cell function** - measure specific Ab reponses to known pathogens/immunisations e.g. tetanus, HIB, S pneumonia; if low then immunise and repeat measurement in 6-8 weeks.

Answer 64

Gamma band shows antibodies - this one above shows absence so this could be Bruton's

Answer 65

1. **Aggressive prophylaxis / treatment of infection** 2. **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 3. **Immunisation** - for selective IgA deficiency, not otherwise effective because of defect in IgG antibody production HSCT not required as you can keep replacing antibodies instead.

Answer 66

1, 2 2, 4 3, 3 4, 1