L23 - Immunodefiency

Question 1

primary vs secondary immunodefiency

Answer 1

primary/inherited:
caused by genetic defects –> defects in cells and mediators of innate or adaptive immune system

secondary/aquired:
caused by either:
- infection with agents/diseases that depletes immune cells
- malnutrition
- immunosuppressive drugs

Question 2

why does the immune system being a complex network affect function

Answer 2

disruption of one component/pathway can impact others

Question 3

what is congenital agammaglobulinemia

Answer 3

X-linked primary immunodefiency

= genetic disorder in BTK gene leading to severe immunodefieincy

Question 4

name of gene that causes XLA - X-linked agammmaglobulinemua

Answer 4

BTK

= defective Bruton tyrosine kinase enzyme

= needed for B cell maturation

Question 5

describe how XLA causes B cell defects

Answer 5

genetic disorder disrupts BTK gene producing a defective enzyme

B cell maturation is blocked at pre-B cell stage

= no mature B-cells in circulation
= absence of antibodies

Question 6

how does the low level of immunoglobulins/antibodies in XLA cause disease

Answer 6

succeptible to pyogenic/bacterial infections –> pus forming

Question 7

clincial signs of somone with XLA

Answer 7

absent or tiny tonsils and lymph nodes

= usaully contain B-cells

Question 8

how does normal class switching happen fopr antibody isotopes in healthy people

Answer 8

1. T-helper cells express CD40 that binds to B cells
2. stimulate class switching by RDG recombinase and somatic hypermutation

Question 9

what happens in Hyper-IgM syndrome

Answer 9

defect in B cell class swicth recombination

= IgM serum levels elavated and other isotypes at very low concs

Question 10

most common cause of Hyper-IgM syndrome

Answer 10

CD40L defiency due to X-linked disorder

Active T-cells express CD40 ligand –> binds to CD40 on B-cells to stimulate class switching and affinity maturation

= no germinal centres BUt enlarged lymph nodes

Question 11

why is Hyper-IgM syndrome. problem

Answer 11

IgG is most abundant antibody in body
- opsonies bacteria
- activates complement

= No IgG –> vulnrable to bacterial infection

IgM cannot undergon somatic hypermutation = low affinity

can also not cross placenta –> no maternal protection for infants

Question 12

what is sevre combined immunodefieincy - SCID

Answer 12

defects in T-cell devlopment lead to

Question 13

why is IgM not enough to tackle disease

Answer 13

the fisrt antibdoy produced when in contact with new antigen

low affinity due to no somatic hypermutation

= produced before B cells enter germinal centres –> site of SM

Question 14

name the most common form of severe combined immunodefiency - SKID

Answer 14

X-linked SKID

= IL2RG gene –> codes for gamma chain/y of cytokine receptors

Question 15

describe how the IL2RG gene mutation causes SKID

Answer 15

codes the common gamma chain (γc) in key cytokine receptors

= receptor cannot transmit signals inside the cell even if the cytokine binds

Question 16

role of IL-7 in t-cell devlopment

Answer 16

Promotes V(D)J recombination –> generates diverse TCRs for endless antigens

also involved in positive/negative selction of T cells in thymus

= defiencies or dysfunctional signalling in SKID cause major problems

Question 17

how do mutations in the IL2RG gene in X-linked SKId cause immunodefieincy

Answer 17

disrupts signalling of key cytokines as they cannot cause intracellular signalling

• IL-7 is essential for T cell development in the thymus.
• IL-15 is essential for NK cell development

B cells still develop since early development doesn’t rely on γc
= need T-cell help to function properly = class switching + memory

Without T cells, B cells can’t produce effective antibodies.

Question 18

how many live births obtain SKID

Answer 18

1 in 50,000

= more common in males due to X linked

Question 19

clinical symtpoms of SKID

Answer 19

very small thymys –> where T-cells are meant to develop

even if B cells are present they cannot function properly without T-cell help

Question 20

name the form of SCID that is caused by defects in development of the thymus

Answer 20

DiGeorge anomoly

= congenital disorder caused by deletion on chromosome 22 at 22q11.2.

Question 21

what do the deletions on chromosome 22 in DiGeorge anomoly cause

Answer 21

defect in thymus development in embryogeneis

= impairs signaling pathways that guide pharyngeal pouch development

thymys transplant into thigh/leg is required to treat

Question 22

what are Tregs

Answer 22

regulatory CD4 T-cells that suppress excessive immune responses

= suppress self-reactive T cells that escape negative selection in thymus

Question 23

what is IPEX

Answer 23

X-linked immunodefiency syndrome

= mutations in Foxp3 gene

codes for transcription factor needed for Tregs

Question 24

hwo do mutations in Foxp3 gene in IPEX cause problems

Answer 24

self-reactive T-cells are free to cause autoimmune disease

Question 25

what is ALPs

Answer 25

autoimmune syndrome mutations in Fas or FasL prevents activation of apoptosis in lymphocytes

Question 26

how do mutations in Fas or FasL cause problems

Answer 26

uncontrolled lymphopcyte proliferation = enlarged spleen and lymph nodes

Question 27

what is and how does Familial haemphagocytic lymphohistocytosis (FHL) cause primary defects in immune regulation

Answer 27

mutations in one of several genes that causes defects in release of lytic granules in CD8/NK 1. T-cells activated but cannot mount cytotoxic response = IFN-y still produced 2. excess IFN-y hyperactivates macrophages = damage and phagocytose blood vessels = tissue damage = often fatal

Question 28

define a syndrome

Answer 28

group of symtpoms that consistantly appear together

Question 29

describe chronic granulomatous disease (CGD)

Answer 29

defective NADPH oxidase = no superoxide anions or hydrogen peroxide made ---> ROS disrupted mcrobes persist in phagosomes = granulomas form to control infection = highly succeptible to bacterial/fungal infection

Question 30

what forms as a result of defects in NADPH oxidase

Answer 30

granulomas = phagocytes cannot kill microbe = granuloma made to contain

Question 31

describe how mutations in LAD1 cause leukoycte adhesion deficiency (LAD)

Answer 31

mutations in LAD1 that codes for CD18 polypetide --> a componet in phagocyte receptors 1. defective CR3 --> cannot bind to opsonised microbes for phagocytosis 2. defective LFA-1 --> cell adhesion molecule = allows phagocytes to migrate from blood to site of infection/into tissues = patients devlop severe bacterial infections

Question 32

what specific type of bacteria do fecienies in complement factors for MAC cause - C5-9

Answer 32

Neisseria = Neisseria lacks thick capsules or other defenses that efficiently block MAC insertion

Question 33

what percentage of people with complement deficinecies in MAC factors obtain Neiseria infections

Answer 33

50%

Question 34

what is the most common cause of immunodeficiny globally and decsfribe the 'viscous cycl'

Answer 34

malnutrition Malnutrition → Weak immunity → More infections → Worse malnutrition → Death risk

Question 35

how do Glucocorticoids - immune suppresants cause secondary immunodeficieny

Answer 35

Block inflammatory cytokines IL-1, TNF-α Inhibit dendritic/T-cell activation, and stabilize mast cells = used to suppress immune system --> post organ transplant

Question 36

what is the 2nd most common cause of immunosuppression world wide and how many deaths a year

Answer 36

HIV - AIDs 2.1 million deaths annually

Question 37

how many CD4+ T cells are present per µl in middle stage of AIDs

Answer 37

>500µl = succetible to very mild conditions = oral candidisis and recuurent herpes virus outbreaks

Question 38

how many CD4+ T cells are present per µl in the final stage of AIDs

Answer 38

>200µl = succetible to life-threatening infections

Question 39

summarise primary vs secondary immunodeficiencies

Answer 39

primary: GENETIC defects cause variety of mutations --> different components of immune system effected Secondary: AQUIRED as consequence of disease,malnutrition or drugs