28 - Immunodeficiency Flashcards

You may prefer our related Brainscape-certified flashcards:
1
Q

what is immunodeficiency?

A

conditions caused by defects in one or more components of the immune system

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

list the two classifications of immunodeficiency

A

primary/ congenital
secondary/ acquired

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

describe the classifications of immunodeficiency

A

primary/ congenital
- condition resulting from a genetic or developmental defect
- present at birth, mostly inherited, though may not be observed until later

secondary/ acquired
- originate as a result of malnutrition, cancer, drug treatment, infection
- more common
- result in immunosuppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

describe the general clinical features of PIDs/ primary immunodeficiencies

A

recurring infections
- e.g. UTIs, otitis media, gastroenteritis = affecting the urinary tract, GI tract and ear
- thrush and fungal infections

failure to thrive for a baby

severe infections with unusual pathogens, occurring in unusual sites - wouldn’t occur in immunocompetent individuals

needing a higher dose or i.v. delivery of antibiotics

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

describe the different general causes of PIDs - innate? adaptive?

A

for innate immune system = caused by a defect in phagocytic or complement function

for adaptive immune system = disorders affecting T and/or B cells, antibody production and cell-mediated immunity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what is the relationship between haematopoiesis and PIDs?

A

defects in the earlier stem cells (e.g. HSCs, early progenitor cells) affect more of the immune system - greater downstream effects

defects in later stage haematopoietic cells show a more restricted pathology - e.g. affecting just T or B cell lineages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what are the four types of immune dysfunction?

A

phagocytic disorders - e.g. chronic granulomatous disease

disorders affecting B cell function and antibody production - e.g. XIA/ X-linked agammaglobulinemia

thymic epithelial cell mediated dysfunction - e.g. DiGeorge syndrome

combined T and B cell immune dysfunction - e.g. WAS/ Wiskott-Aldrich Syndrome, SCID`

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

examples of major B cell disorders?

A

XIA = X-linked agammaglobulinemia/ Bruton’s disease

common variable immunodeficiency/ CVID

Selective IgA deficiency

IgG2 subclass deficiency

specific Ig deficiency with normal Igs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

examples of adaptive PIDs?

A

XIA = X-linked agammaglobulinemia/ Bruton’s disease

selective IgA immunodeficiency

SCID = severe combined immunodeficiency

DiGeorge syndrome

WAS = Wiskott-Aldrich syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is XIA?

A

X-linked agammaglobulinemia or Bruton’s disease

X-linked recessive immunodeficiency which affects B-cell development

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what causes XIA? what effect does this have on immune cells?

A

BTK gene on X chromosome that encodes Bruton’s tyrosine kinase is mutated - BTK is needed for downstream signalling of B cells for development

BTK mutation blocks B-cell signalling = blocks B-cell development = stops at pre-B cell stage

lack of B cells and antibody production

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

clinical consequences of XIA

A

recurrent severe infections
- susceptible to resp, GI tracts & ear infections

risk of autoimmunity

symptoms appear early in life

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

diagnosis of XIA? immune cell levels, other tests?

A

immune cell levels:
- low/ absent B cells, plasma cells and Igs
- normal T cells, NK cells and T-cell mediated responses = this is a B cell restricted ID

diagnosis by flow cytometry or immunoglobulin immune-electrophoresis
- patient’s serum is placed on matrix of a small plate, and components of serum migrate according to charge, stimulated by electricity
- sample moves and separates components = absence of Igs indicates XIA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

treatment for XIA?

A

i.v. administration of exogenous Igs - polyclonal Igs from donor

antibody therapy needed for severe infections but NO live vaccines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is selective IgA deficiency?

A

absence of IgA - needed for protecting mucosal surfaces

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

selective IgA - diagnosis?

A

low serum and secretory IgA levels

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

selective IgA - presentation?

A
  • mostly asymptomatic
  • sometimes infections of respiratory, urogenital or GI tract, increased incidence of allergic reactions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what are combined immunodeficiencies? examples?

A

IDs affecting both T and B cells

examples:
- DiGeorge syndrome
- Wiskott-Aldrich syndrome/ WAS
- Ataxia-telangiectasia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

SCID - potential causes?

A

common cytokine receptor gamma-chain defect
RAG 1 & 2 defect
ADA/ adenosine deaminase deficiency

20
Q

describe the causes of SCID

A
  1. common cytokine receptor gamma-chain defect
    - lots of cytokines (e.g. IL-2, 4, 7, 15) share the same gamma chain as part of their cytokine receptor
    - defect affects transduction signalling and their functions for B and T cells
  2. RAG 1& 2 defect
    - defect in the RAG enzymes involved in TCR and BCR gene rearrangement = blocks their development
  3. ADA/ adenosine deaminase deficiency
    - leads to accumulation of deoxy-ATP = becomes toxic for dividing thymocytes = affects T-cell production
21
Q

cellular presentation of SCID

A

T, B and NK cells present in low numbers = low total lymphocyte count

  • B cells can be normal to absent
  • NK cells can be absent especially if IL-15 receptor is affected by gamma chain defect
  • reduced function and proliferation of T cells
22
Q

diagnosis of SCID

A

different variations and presentation of SCID - can have absence or presence of T, B and NK cells in different combos

verified by flow cytometry

low T cells can influence/ lower B cell numbers

23
Q

treatment for SCID

A

patient isolation to prevent infections

**blood products ** from donors = blood needs to be checked for presence of pathogens

i.v. Ig replacement

infection prophylaxis with antibiotics

bone marrow/ HSCs transplant = replenishing bone marrow with healthy precursors, engraftment

gene therapy to correct gamma chain or ADA defective genes

24
Q

what is DiGeorge syndrome? what is the cause?

A

complete absence of thymus or thymic hypoplasia due to chromosome 22q11 deletion

25
Q

presentation of DiGeorge syndrome?

A

dysmorphic face: cleft palate, low-set ears, fish-shaped mouth

hypocalcaemia, cardiac abnormalities, thyroid problems

presentation can vary
- complete DG = absence of thymus
- incomplete DG = thymic hypoplasia
leads to partial/ complete absence of T cell development

26
Q

treatment of DiGeorge?

A

with complete DG - thymus transplant
- involves receiving slices of a normal thymus which are tested and transplanted into recipient with complete DG

27
Q

what is Wiskott-Aldrich syndrome/ WAS?

A

X-linked adaptive primary immunodeficiency caused by a defect in WASP protein

28
Q

cause of Wiskott-Aldrich syndrome

A

defect in WASP - protein involved in actin polymerisation, mutation causes incorrect cytoskeleton remodelling = incorrect signalling and progressive loss of T cells

29
Q

clinical presentation of Wiskott-Aldrich syndrome

A

thrombocytopenia
eczema
recurrent infections
progressive loss of T cells and decrease in T cell proliferation = worsens condition
low antibody production

30
Q

examples of innate immunodeficiencies?

A

Chronic Granulomatous Disease
Chediak Higashi Syndrome
Leukocyte Adhesion Deficiency

31
Q

relationship between hemopoiesis and innate PIDs/ immunodeficiencies?

A

affect production of myeloid cells from myeloid progenitors - e.g. granulocytes, neutrophils, macrophages…

defects higher up affect more cells

defects later on affect specific cells/ specific groups of immune cells

32
Q

chronic granulomatous disease - cause? effect?

A

cause:
mutation in phagocyte oxidase/ NADPH components

effect:
affects phagosome oxygen-dependent killing = no oxidative killing = microbes continues living in PL

33
Q

chronic granulomatous disease - effect?

A

affects phagocytosis in phagolysosomes as it’s oxygen-dependent = leads to defective oxidative killing of phagocyte microbes

no killing of microbe in PL via superoxidase ions, ROS and NOS

microbe lives within PL

34
Q

chronic granulomatous disease - presentation?

A

granulomas - areas full of immune cells/ macrophage trying to control and isolate the pathogen to clear it

a mass of granulation tissue

35
Q

chronic granulomatous disease - diagnosis?

A

clinical presence of granulomas

nitro blue tetrazolium reduction test = reduces NADPH components in phagolysosomes
- normally activity leads to change in dye colour
- in CGD there’s no change

dihydrorhodamine assay
- becomes fluorescent in presence of NAPDH activity and shift assay signal to the right = no shift/ fluorescence in CGS

36
Q

Chediak-Higashi syndrome - cause? effect?

A

cause:
defect in LYST gene that regulates lysosome traffic - affects phagocytosis and phagosome-lysosome fusion

effect:
defective PL fusion contributes to repeat severe infections, with lack of clearance

37
Q

Chediak-Higashi syndrome - effect?

A

defective PL fusion = repetitive severe infections, can’t clear infections

38
Q

Chediak-Higashi syndrome - diagnosis

A

decreased number of neutrophils

neutrophils have giant granules due to defective PL fusion

39
Q

Leukocyte adhesion deficiency/ LAD - causes? effect?

A

cause:
1. defect in beta 2 chain of integrins = affects LFA-1 and Mac-1 integrins

  1. defect in selectin ligand

effect:
- affects contact and adhesion of neutrophils to endothelium = affects transmigration of neutrophils to site of infection

40
Q

leukocyte adhesion deficiency/ LAD - effect?

A

affect contact and adhesion between neutrophils and endothelium before transmigration of immune cells to the site of damage

41
Q

leukocyte adhesion deficiency/ LAD - clinical presentation?

A

skin problems
GI tract infections
perianal ulcers

42
Q

leukocyte adhesion deficiency/ LAD - diagnosis?

A

low neutrophil chemotaxis - not moving properly

low integrin expression on phagocytes - determined by flow cytometry of a blood sample

43
Q

treatment for primary immunodeficiencies?

A

prevent infection - isolation, prophylactic treatment, (not live) vaccines

nutrition

replacing the defective/ absent component of the immune system - e.g. bone marrow/ thymus transplant

gene therapy

44
Q

describe gene therapy as a PID treatment

A

bone marrow stem cells are taken from patient

mutated/ defective immune cell progenitors are isolated and infected with a virus vector to introduce a correct copy of the mutated gene

immune progenitors take up the correct version of the defective gene - re-inserted into patient, resolves dysfunction of the immune system

45
Q

what are secondary immunodeficiencies - examples?

A

secondary IDs - acquired, not caused by a particular mutation; it’s a result of another condition

examples:
- HIV depletes CD4+ T cells
- malnutrition
- cancer chemotherapy
- immunosuppression from transplants

46
Q

treatment for HIV?

A

HAART/ highly active antiviral therapy
PrEP/ pre-exposure prophylaxis - taken to prevent getting HIV, stops transmission