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Path - Immuno > primary immunodeficiencies > Flashcards

primary immunodeficiencies Flashcards

1
Q

what is the purpose of:

cytokines and chemokines

A

Cells secrete cytokines and chemokines to regulate immune response

Cells express cytokine/chemokine receptors that allow them to home to sites of infection

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2
Q

what is the purpose of:

pattern recognition receptors

A

to allow detection of pathogens at site of infection - PRRs recognise PAMPs on the organisms.

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3
Q

what is the purpose of:

Fc receptors

A

to allow detection of immune complexes

They are found on many immune cells and bind to fc region on antibodies that have opsonised pathogens, allowing activation of phagocytosis or cytotoxic mechanisms

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4
Q

how do macrophage interact with T cells?

A

Capable of presenting processed antigen to T cells

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5
Q

what are the types of phagocyte deficiency?

A
  1. Failure to produce neutrophils
  2. Defect of phagocyte migration
  3. Failure of oxidative killing mechanisms
  4. Cytokine deficiency
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6
Q

what are the mechanisms of failure to produce neutrophils?

give examples of conditions and their aetiology?

A

Failure of stem cells to differentiate along myeloid or lymphoid lineage:

  1. Reticular dysgenesis – autosomal recessive severe SCID
  2. Specific failure of neutrophil maturation
    A. Kostmann syndrome - autosomal recessive severe congenital neutropenia

B. Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks, so milder tha kostmann

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7
Q

what are the mechanisms of Defect of phagocyte migration?

give examples of conditions and their aetiology?

A

Leukocyte adhesion deficiency (LAD)
Deficiency of CD18 (b2 subunit of integrin)

you will see absence of pus formation

So immunodeficient despite very high neutrophil count

CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

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8
Q

what are the mechanisms of Failure of oxidative killing mechanisms ?

give examples of conditions and their aetiology?

A

Chronic granulomatous disease is an example condition

Absent respiratory burst

  • Deficiency of one of components of NADPH oxidase
  • Inability to generate oxygen free radicals results in impaired killing

Excessive inflammation

 - Persistent neutrophil & macrophage accumulation
  - Failure to degrade antigens

Granuloma formation
Lymphadenopathy and hepatosplenomegaly

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9
Q

what tests are done in the Investigation of chronic granulomatous disease?

A 
2 tests:
Nitroblue tetrazolium (NBT) test 
Dihydrorhodamine (DHR) flow cytometry test

They are technically testing for the presence of neutrophils;
Activate neutrophils – stimulate respiratory burst and production of hydrogen peroxide

NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide

DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

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10
Q

what are the mechanisms of Cytokine deficiency?

A

IL12, IL12R deficiency
IFNg or IFNg R deficiency

Mycobacteira infected macrophages stimulated to produce IL12
IL12 induces T cells to secrete IFNg
IFNg feeds back to macrophages & neutrophils
Stimulates production of TNF
Activates NADPH oxidase
Stimulates oxidative pathways

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11
Q

what conditions are those with cytokine deficiency more suscpetible to? why?

A

These people get recurrent TB

because IL12- IFNg network important in
control of mycobacteria infection - but is deficient in this case

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12
Q

how do we manage phagocyte deficiencies?

A

Aggressive management of infection

- Infection prophylaxis
- Oral/intravenous antibiotics as needed

Definitive therapy:
1.Haematopoietic stem cell transplantation

2.Specific treatment for CGD - IFNg therapy

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13
Q

what receptors do NK cells express? what is their response?

A

Inhibitory receptors recognise self-HLA molecules that prevent inappropriate activation by normal self

Activatory receptors including natural cytotoxicity receptors recognise heparan sulphate proteoglycans -> NK then causes:

Cytotoxicity
Cytokine secretion
Contact dependent regulation

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14
Q

what are the types of Natural killer cell deficiencies?

A
  1. Classical NK deficiency
    Absence of NK cells within peripheral blood
  2. Functional NK deficiency
    NK cells present but function is abnormal
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15
Q

what do Natural killer cell deficiencies lead to?

A

Susceptibility to Viral infection:

	Herpes virus infection
		Herpes Simplex virus I and II
		Varicella Zoster virus
		Epstein Barr virus
		Cytomegalovirus
	Papillomavirus infection
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16
Q

what are the treatments for Natural killer cell deficiencies?

A

Prophylactic antiviral drugs such as acyclovir or gancyclovir

Cytokines such as IFN-alpha to stimulate NK cytotoxic function

Haematopoietic stem cell transplantation in severe phenotypes

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17
Q

what are the Three pathways of complement activation?

A

Classical - C1 C2 C4

MBL - C4 C2

Alternate

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18
Q

how does the classical complement pathway work?

A

Formation of antibody-antigen immune complexes

Results in change in antibody shape – exposes binding site for C1

Binding of C1 to the binding site on antibody results in activation of the cascade

Dependent upon activation of acquired immune response (antibody)

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19
Q

how does the MBL pathway work?

A

Activated by the direct binding of MBL to microbial cell surface carbohydrates

Directly stimulates the classical pathway, involving C4 and C2 but not C1

Not dependent on acquired immune response

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20
Q

how does the alternative pathway work?

A

Bacterial cell wall fails to regulate low level of spontaneous activation of alternate pathway
eg lipopolysaccharide of gram negative bacteria
teichoic acid of gram positive bacteria

Not dependent on acquired immune response

Involves factors B, D and Properidin

Factor H – control protein

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21
Q

______ is the major amplification step in the complement cascade. what does it lead to

A

Activation of C3

Triggers the formation of the membrane attack complex via C5-C9

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22
Q

what are the other roles of complement?

A

Opsonisation of pathogens to promote phagocytosis

Activates phagocytes

Punches holes in bacterial membranes

Increases vascular permeability and cell trafficking to site of inflammation

Promotes clearance of immune complexes

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23
Q

what does complement deficiency lead to?

A

Complement deficiency
Susceptibility to bacterial infections, especially encapsulated bacteria (NHS)
N - Neisseria meningitides – esp properidin and C5-9 deficiency
H- Hemophilus influenzae
S- Streptococcus pneumoniae

Classical pathway deficiency (C2)
Susceptibility to SLE 
Failure of phagocytosis of dead cells
Increased nuclear debris
Failure to clear immune complexes
Immune complex deposition in blood vessels

MBL deficiency:
MBL2 mutations are common but not usually associated with immunodeficiency

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24
Q

Active SLE leads to consumption of _____

A

C3 and C4

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25
Q

what is the role of Nephritic factors ? what are they?

A

Nephritic factors are auto-antibodies directed against components of the complement pathway

Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption

Often associated with glomerulonephritis (classically membranoproliferative)

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26
Q

how are Investigation of complement deficiencies done?

A

CH50 classical pathway
AP50 alternative pathway

C3, C4 routinely measured

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27
Q

what does CH50 and AP50 mean?

A

checking / testing for the haemolytic (erythrocyte lysis) activity of the classical and alternate pathways.

28
Q

how is Management of patients with complement deficiencies conducted?

A

Vaccination:
- Meningovax, Pneumovax and HIB vaccines

Prophylactic antibiotics
Treat infection aggressively
Screening of family members

29
Q

how is Management of patients with complement deficiencies conducted?

A

Vaccination:
- Meningovax, Pneumovax and HIB vaccines

Prophylactic antibiotics
Treat infection aggressively
Screening of family members

30
Q

what would be the result of the NBT and DHR test in children with CGD and why?

A

NBT wont turn blue

DHR wont fluoresce

because no H202 has been produced (no respiratory burst because though neutrophils are present, components of the NADPH oxidase are missing! )

31
Q

which are the cells in the adaptive immune system?

and of the innate?

A

B cells
T cells

Innate: everything else including soluble components; Cytokines and chemokines

32
Q

which is the most common classical pathway complement deficiency?

A

C2 - MOST COMMON

33
Q

What is the aetiology of C1q deficiency and how does it present?

A

Inherited form of complement deficiency that tends to present with SLE in childhood

34
Q

what would be the CH50 and AP50 result with C9 or C7 deficiency?

A

both reduced as problem lies in the common pathway

35
Q

what would be the ivx resutls in someone with SLE?

A

○ If someone has acquired SLE, they will have low C4 and possibly low C3

○ They may also have some dysfunction of the CH50 pathway because they don’t have much complement left

36
Q

C3 deficiency with presence of a nephritic factor is a STEROTYPICAL presentation of?

A

membranoproliferative nephritis and abnormal fat distribution

37
Q

properidin deficiency and C5-9 deficiency are associated with susceptibility to which infections?

A

N. meningitidis infection

encapsulated bacteria - NHS

38
Q

Recurrent infections with high neutrophil count on FBC but no abscess formation is consistent with?

A

Leukocyte adhesion deficiency

39
Q

Recurrent infections with hepatosplenomegaly and abnormal dihydrorhodamine test (does not fluoresce)
formation is consistent with?

A

Chronic granulomatous disease

40
Q

Recurrent infections with no neutrophils on FBC is consistent with?

A

Kostmann syndrome

41
Q

Infection with atypical mycobacterium. Normal FBC is consistent with?

A

IFN gamma receptor deficiency

42
Q

Severe chicken pox, disseminated CMV infection, is consistent with?

A

Classical natural killer cell deficiency

43
Q

Recurrent infections when neutropenic following chemotherapy but previously well is consistent with?

A

MBL deficiency

44
Q

list the types of primary immunodeficienciese in order from most to least common ?

A

B cell 50%

Mixed - T+B cell

Phagocytic

T cell - least common

45
Q

Immunodeficiencies affecting T cells, cause which type of infections?

A

intracellular - eg viruses and mycobacteria

46
Q

list some examples of primary immunodeficiencies affecting the innate immune system

A

CGD - chronic granulomatous dis..

PNH - paroxysmal nocturnal haemoglobinuria

leukocyte adhesion deficiency

G6PD deficiency etc

47
Q

the follwoing are associated with which infections:

A - C1q, C1r, C2, C3, C4,

B - C5, C6, C7, C8, C9, Properdin, factor D

C - MBL

A

A - pyogenic bacteria

B - Neisseria Meningitidis in partiicular

C - None

48
Q

PNH is caused by?

A

malfunctioned complement control

due to PIG-A mutation

causes complement mediated red cell lysis

49
Q

what is the genotype of CGD?

A

Remeber it is polygenic. has these 2 forms:

X-linked
Autosomal recessive

50
Q

what is the genotype of Leukocyte adhesion deficiency (LAD)?

A

3 types
LAD I, II, III

type I is the defect. in cd18 b2 integrin

51
Q

the divalent antibody present within mucous which helps provide a constitutive barrier to infection is ___ ?

A

IgA

52
Q

which B cells are generated rapidly following antigen recognition and are not dependent on CD4 T cell help?

A

IgM secreting plasma cells

53
Q

which B cells are dependent on the help of CD4 T cells?

A

IgG secreting plasma cells

54
Q

name the cell:

Derived from monocytes and resident in peripheral tissues

A

Macrophages

55
Q

name the cell:

Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms

A

Neutrophils

56
Q

name the cell:

Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity

A

NK cells

57
Q

name the cell with this function:

Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells

A

Dendritic cell

58
Q

what is the Anatomical sites of interaction between naïve lymphocytes and microorganisms?

A

Secondary lymphoid organs

Spleen
Lymph nodes
Mucosal associated lymphoid tissue

59
Q

name the cell with this function:

Express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA class I molecules

A

CD8 T cells

60
Q

name the cell with this function:

Subset of lymphocytes that express Foxp3 and CD25

A

T regulatory cells

61
Q

name the cell with this function:

Subset of cells that express CD4 and secrete IFN gamma and IL-2

A

Th1

62
Q

name the cell with this function:

Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells

A

T follicular helper (Tfh) cells

63
Q

Name this place:

An area within secondary lymphoid tissue where B cells proliferate and undergo affinity maturation and isotope switching

A

Germinal centre

64
Q

name the protein:

Binding of immune complexes to this protein triggers the classical pathway of complement activation

A

C1

65
Q

name the protein:

Binds to microbial surface carbohydrates to activate the complement cascade in an immune complex independent manner

A

MBL

66
Q

name the protein:

Part of the final common pathway resulting in the generation of the membrane attack complex

A

C9

67
Q

name the protein:

Cleavage of this protein may be triggered via the classical, MBL or alternative pathways

A

C3

Path - Immuno (11 decks)

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