Immunodeficiency

Question 1

What are primary immunodeficiencies?

Answer 1

inherited genetic defects in the immune system

Question 2

What are secondary immunodeficiencies?

Answer 2

The effects of external agents or breakdown in other body systems which then affect the immune system. Secondary IDs more common than primary IDs

Question 3

Name three primary IDs affecting the innate immune response.

Answer 3

Chronic granulomatous disease (CGD), Leukocyte adhesion deficiency and complement deficiencies.

Question 4

What is the pathophysiology of CGD?

Answer 4

where NADPH oxidase defect affecting phagocytic cells; phagocytosis can occur however the cells are unable to mount a respiratory burst. Multiple components on different autosomal chromosomes constitute NADPH however there is one located on X chromosome (X linked inheritance). If left untreated, patients die from overwhelming chronic infections and require a bone marrow transplant.

Question 5

What is leukocyte adhesion deficiency?

Answer 5

beta2 integrin defect affecting neutrophils and monocytes

Question 6

Where could mutations causing complement deficiencies be located?

Answer 6

In MHC-III; C3 defects would be most deleterious.

Question 7

Name the primary IDs affecting B cells

Answer 7

Selective IgA deficiency, Hyper-IgM syndrome and X-linked agammaglobulinaemia

Question 8

What is selective IgA deficiency?

Answer 8

The most common primary ID, dependent on nature of mutation whether IgA is absent or present in low levels; asymptomatic with no pathological consequences.

Question 9

what is hyper-IgM syndrome caused by?

Answer 9

Caused by number of different mutations but most common mutations on CD40 on B cells and CD40L on T helper cells. Class switching is dependent on the interaction between CD40 on B cells and cD40L on T cells. Hyper-IgM syndrome then arises, with higher levels of IgM and class switching cannot occur. Plasma cells can only produce IgM.

Question 10

What is X-linked agammaglobulinaemia caused by?

Answer 10

Bruton’s tyrosine kinase defects.

Question 11

Name the Primary IDs of T cells.

Answer 11

Wiskott-Alrich syndrome, DiGeorge syndrome.

Question 12

What causes wiskott-Alrich syndrome?

Answer 12

WASP defect; Xlinked. No funtional wiskott-alrich syndrome protein

Question 13

What is SCID and what causes it?

Answer 13

Severe combined immunodeficiency; mutations in Gamma c (IL receptors 2&4), RAG (recombination activating genes) ADA (adenosine deaminase), artemis and JAK-3. Affects both T and B cells; no functional cells. Profound recurrent infections.
Gamma c chain = T-B+NK-SCID - nature of mutation does not affect B cells
JAK-3 (a kinase) = T-B+NK- phenotype
ADA: T-B-NK- SCID; most profound.

Question 14

What is DiGeorge syndome

Answer 14

Defect in TBX1 gene, characterised by athymia; no T cells plus facial developmental defects; TBX1 is implicated in thymus development; can be partial/full DiGeorge dependent on the nature of the mutation.

Question 15

What causes secondary IDs?

Answer 15

Malnutrition; protein-calorie malnutrition and lack of dietary elements such as iron and zinc.
Loss of cellular/humoral components; lymphocytes passively lost into the intestine in intestinal lymphangiesctasia: proteins (antibodies) lost into the urine in nephrotic syndrome
Tumours: The direct effect of tumours of the immune system
Cytotoxic drugs/irradiation: widely used for inhibiting tumour cell growth but simultaneously damage immune cells: treatment is not selective.
Infections: Malaria inhibits the development of immune responses, HIV infecting CD4+ cells resulting in AIDS when CD4+

Question 16

How does HIV infect cells?

Answer 16

Must bind to CD4 through its gp120 surface glycoprotein of 120 kDa. HIV-1 then enters the cell by direct fusion through using a correceptor-chemokine receptors such as CCR5 for macrophages and CXCR4 for T cells. HIV has a high mutation rate. T-cell/macrophage-trophic variants exist (polymorphism)

Question 17

What occurs following HIV infection?

Answer 17

Increase in plasma HIV concentration after first few weeks (primary infection) INF increases, CD4 increase, specific HIV antibodies produced (seroconversion following primary infection); effective immune repsonse however not a full infection clearance -asymptomatic period. Without treatment plasma virus concentration increases. CD4 decreases. When CD4

Question 18

What are IDs characterised by?

Answer 18

Opportunistic infections;
Cytomegalovirus
M. tuberculosis
Candida albicans and Pneumocystis jiroveci
Toxoplasma gondii

Question 19

How are IDs treated?

Answer 19

Antibiotics, gammaglobulins for antibody deficiencies, cell replacement therapy (hematopoietic stem cells, foetal liver and thymus grafts) and gene therapy (Gamma c chain and ADA deficiencies.