Case 29: IL1R Associated Kinase 4 Deficiency

Question 1

how are microorganisms detected by macrophages?

Answer 1

PAMPs on pathogens are recognized by PRRs on macrophages and neutrophils which take up the pathogen and destroy it

PRRs are also present on dendritic
cells, whose function is to present antigen to and activate naive T cells

Question 2

which cells form the link between the innate and adaptive immune response?

Answer 2

dendritic cells

Question 3

what are TLRs?

Answer 3

toll-like receptors

theyre a type of PRR on he cell surface
and in the membranes of endosomes

they enable cells of the innate immune
system to detect and respond to a wide variety of pathogens

Question 4

what do TLRs recognize?

Answer 4

they recognize microbial
nucleic acids, such as unmethylated bacterial DNA and long double-stranded
RNA, as well as molecules specific to particular classes of microorganisms, such
as the bacterial lipopolysaccharide (LPS or endotoxin) characteristic of Gramnegative
bacteria and the protein flagellin of bacterial flagella

Question 5

what does TLR activation lead to?

Answer 5

their activation leads to enhancement of
the antimicrobial activity of macrophages and neutrophils, and the secretion of
cytokines by macrophages, which help attract more macrophages and neutrophils
out of the blood and into the site of infection

TLR signaling also induces the maturation of tissue dendritic cells
and their migration to peripheral lymphoid tissues such as lymph nodes, where
they encounter and activate antigen-specific T cells

Question 6

what happens during dendritic cell development?

Answer 6

up regulation of the production of co-stimulatory molecules like CD40, CD80, and CD86 which are necessary for T cell activation

they also produce chemokines and cytokines that help induce adaptive immune
responses, such as the pro-inflammatory cytokines TNF-
α, IL-1, IL-6, and IL-12

Question 7

what is needed for differentiation of TH1 cells?

Answer 7

the upregulation of co-stimulatory molecules and of
IL-12 production as a result of TLR stimulation is essential for dendritic cells to be
able to induce the differentiation of TH1 effector functions, such as the secretion of
IFN-γ, in CD4 T cells.

Question 8

what does the IL1R signal transduction pathway involve?

Answer 8

1. IL1R and TLRs share a common signal transduction pathway that involves the adaptor protein MyD88, the signaling intermediate TRAF-6,
   and the receptor-associated protein kinases IRAK1 and IRAK4
2. activation of IL1R and TLRs leads to recruitment of MyD88 to the receptor followed by the recruitment and activation of IRAK4, the initial protein kinase in the TLR signal transduction pathway
3. this is followed by recruitment of IRAK1 and TRAF-6
4. then this pathway splits and one branch activates MAP kinases and the other activates NFκB
5. both MAPK and NFκB lead to TNFα and IL-6 production

Question 9

why is IRAK4 important?

Answer 9

we need it to elicit a response to TLR ligands

without IRAK4, signaling via the NFκB pathway is blocked without it and then you can’t make IL-6, IL-12, and TNF-α

so IRAK4 is necessary for innate immunity!

Question 10

how is IRAK4 important in adaptive immunity?

Answer 10

antigen-stimulated T cells from mice with inactivated IRAK4 kinase secrete
reduced amounts of IL-17, a cytokine that is important in antibacterial immunity

mice lacking IRAK4 were found to have reduced splenic and peripheral
expansion of CD8 T cells in response to infection with lymphocytic choriomeningitis
virus, suggesting that IRAK4 may be required for optimal antiviral CD8 T-cell
responses in vivo

Question 11

what type of infections are people more susceptible to if they have an IRAK4 deficiency?

Answer 11

pyogenic bacteria

since MyD88 is upstream from IRAK4, patients with MyD88 deficiency also have increased susceptibility o IRAK4 deficiency

Question 12

what is the clinical presentation of someone with IRAK4 deficiency?

Answer 12

• recurrent pyogenic bacteria infections
• normal numbers of B and T cells
• normal serum immunoglobulin levels

Question 13

Douglas’s immune deficiency is characterized by susceptibility to severe,
invasive pneumococcal infection. What other immunodeficiencies are associated
with similar susceptibility to pneumococci?

Answer 13

several immunodeficiencies result in susceptibility to pneumococcal infection – these include defects of innate immunity, including congenital asplenia and defects within the complement pathways

other defects
in the NFκB activation pathway that lies downstream of TLRs and other cell-surface
receptors include NEMO deficiency and mutations in IkB that prevent
its degradation and release of NFκB

in addition, defects of adaptive immunity that
result in impaired antibody production, such as X-linked agammaglobulinemia and common variable immunodeficiency, result in increased
susceptibility to Gram-positive bacteria, such as pneumococci and staphylococci

Question 14

What clue in the history of a patient with recurrent pneumococcal or
staphylococcal infections would favor a possible diagnosis of IRAK4 deficiency?

Answer 14

these infections are usually associated with fever

IRAK4 deficiency, however, leads
to an early block in the TLR/IL-1R signaling pathways and barely detectable or no
TLR-induced production of pro-inflammatory cytokines

the virtual absence of proinflammatory
cytokines and the inability of IRAK4-deficient patients to respond to
what little IL-1 might be produced results in an impaired febrile response

thus, a history of little or no fever associated with recurrent pyogenic infections
supports a possible diagnosis of IRAK4 deficiency

Question 15

What is the clinical course of patients with known defects in IRAK4?

Answer 15

so far, there are too few IRAK4-deficient patients for us to be sure. More cases of
IRAK4 deficiency need to be identified and followed throughout their lives before
conclusions can be drawn

the 18 patients identified so far all show an increased susceptibility
to invasive infections with pyogenic bacteria in childhood

as they mature
into adolescence, however, susceptibility to such infections becomes variable, and
many no longer show significantly increased susceptibility

Question 16

Why might IRAK-deficient patients fail to respond to immunization with
polysaccharide antigens?

Answer 16

the antibody response to polysaccharides seems to require initial signaling via TLR-2
(which recognizes lipoteichoic acid of Gram-positive bacterial cell walls and lipoproteins
of Gram-negative bacteria) and TLR-4 (which recognizes LPS) in dendritic cells

this may be because stimulation of dendritic cells via these TLRs is essential for their
ability to induce the differentiation of T cells (especially TH1) that help B cells to make
the antipolysaccharide antibodies

the response to Pneumovax, for example, seems
to depend on the presence of such TLR ligands in the vaccine. It has been shown
that depletion of endotoxin from the vaccine renders it unable to elicit an antibody
response in mice

Question 17

IRAK4 seems to be involved in signaling from all TLRs. Why has increased
susceptibility to viral infections not yet been documented in human patients?

Answer 17

the answer to this important question is not clear

the production of type I interferons
in response to the ligation of TLRs 7, 8, or 9 is markedly diminished in
IRAK4-deficient patients, and interferon synthesis is variably affected in response
to TLR-3 ligation by long double-stranded RNA

the apparent integrity of the antiviral
defenses in these patients is therefore surprising – one explanation could be that
humans can make relatively intact adaptive immune response to viruses as a result of responses by cytotoxic T cells, which kill the infected cells, and through antiviral antibodies
produced by B cells

there is probably redundancy between the adaptive and
innate immune responses, with (innate system) NK cells cytotoxic for virus-infected
cells being activated by T-cell-derived IL-2 and IFN-γ

other intracellular antiviral
immune responses are produced via activation of the RNA-dependent protein kinase
pathway and via activation of the cytoplasmic protein RIG1 by double-stranded RNA,
which leads to the synthesis of type I interferons

Question 18

How should IRAK4-deficient patients be managed to prevent the recurrence of
invasive infection?

Answer 18

experience in managing these patients is limited

however, they are maintained in
good health into their adolescence by a combination of prophylactic antibiotics and
regular infusions of intravenous immunoglobulin