Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group KIR's and AS

http://www.nature.com/cmi/journal/vaop/ncurrent/full/cmi201042a.html

KIR (Killer Immunoglobulin Receptors) are part of the innate immune system

This is a very interesting paper implicating Natural Killer cells (an appropriate name)
I put together some notes on the KIR's last year, which I'd largely forgotten, but will post them here to maybe give a little background information on the topic.
Cheers David

Natural Killer Cells play a role in the rejection of tumours and virally infected cells. NK cells [cytotoxic T cells (lymphocytes) use the same mechanism] release cytoplasmic cytotoxic granules called perforin which forms pores in the target cell plasma membrane allowing granzymes, a type of serine proteases which activates a series of enzymes, the caspase cascade, that eventually results in the target cell dying by apoptosis (programmed cell death). NK cells do not express T-cell receptors or Pan T marker CD3 or surface immunoglobulin B cell receptors. They usually express the surface markers CD16 (Fc gamma RIII) and CD56 in humans. Note that up to 80% of NK cells also express CD8.

NK cell activity is tightly regulated by activating signals from: -
Cytokines – stress molecules released by virally infected cells, such as interferon or macrophage derived cytokines. NK cells buy time for the adaptive humoral immune response to kick in.
Fc receptor – NK cells along with macrophages and several other cell types express Fc receptors (FcR) molecules that bind the Fc portion of antibodies. Thus NK cells can target cells against which a humoral response has been mobilized causing their lysis through Antibody-dependent cellular cytotoxicity (ADCC).
Activating and inhibitory receptors – a variety of receptors that serve to activate or suppress NK cytolytic activity. These receptors bind to various ligands on target cells both endogenous and exogenous. Inhibitory receptors recognize surface MHC Class I alleles when they present self peptides – the effector cells are trained not to react. When surface MHC Class I molecules are loaded with a bound ligand of viral or cancerous ‘nonself’ then inhibitory receptors may be blocked or fail to bind and activating NK receptors preferentially bind the effected cell and induce apoptosis. KIR (Killer immunoglobulin-like receptors) and LIR (leukocyte immunoglobulin-like receptors) are the main receptors on NK cells that recognise MHC Class I (HLA A,B,C).
Upon release in close proximity to a cell perforin forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter, inducing apoptosis.

KIR : Killer Immunoglobulin-like Receptors and their role in the SpA’s.
KIR’s are a diverse family of cell surface protein receptors found on Natural Killer cells (and a subset of T-cells). They regulate the killing function of these cells by interaction with MHC Class I molecules, which are expressed on all cells. This interaction allows them to detect virally infected or tumour cells that have a characteristic low level of class I MHC on their surface (the “missing self” hypothesis). Most KIR’s are inhibitory, meaning their recognition of MHC suppresses the cytotoxic activity/capacity of their NK cell.

The KIR gene cluster is found on chromosome 19q13.4 within the leukocyte receptor complex (LRC) and constitutes a multigene family whose genomic diversity is achieved through differences in gene content and allelic polymorphisms.
The KIR gene family currently consists of 15 genes (all prefixed KIR); Nomenclature is dependent on whether or not they have 2 (2D) or 3 (3D) immunoglobulin-like domains and whether they possess a short (S) or long (L) cytoplasmic tail.
Two domains long cytoplasmic (inhibitory) tail 2DL1 2DL2 2DL3 2DL4 2DL5A 2DL5B
Two domains short cytoplasmic (activating) tail 2DS1 2DS2 2DS3 2DS4 2DS5
Three domains long cytoplasmic (inhibitory) tail 3DL1 3DL2 3DL3
Three domains short cytoplasmic (activating) tail 3DS1
and two pseudogenes 2DP1 AND 3DP1.

Functionality of the KIR’s have been classified into two types :- activating KIR’s that have a short cytoplasmic tail (2DS AND 3DS), and the capacity to interact with NK cell adaptor proteins such as the enzyme DAP12 ,also called TYROBP (TYRO proteins Tyrosine kinase binding protein) thereby delivering activating signals through an immunoreceptor tyrosine-based activating (ITAM) motif in the short cytoplasmic tail; and inhibitory KIR’s that have a long cytoplasmic tail (2DL and 3DL), which have one or two immunoreceptor tyrosine-based inhibition (ITIM) motifs in their long cytoplasmic tail. 2DL4 is the exception being an activating KIR.

The complexity of KIR’s is compounded by substantial allelic and haplotypic diversity. Each KIR gene has between 4 and 19 alleles and individuals can have different numbers of KIR genes.

To date only class I MHC molecules have been identified as ligands of KIR’s.
In general KIR2D receptors recognize HLA-C alleles, whereas KIR3D receptors recognize HLA-A and HLA-B alleles.

The HLA B antigens are divided between Bw4 and Bw6 epitope specificities (Bw4 and Bw6 are epitopes or accessible antigenic determinants against which antibodies can be raised) which are the binding sites (ligands) for the relevant KIR’s. HLA B27 antigens all have Bw4 epitopes, defined by residues at positions 77-83 which are recognized by the inhibitory receptor KIR3DL1 (and KIR3DL2); with the exception of B27*08 which has a Bw6 epitope.

KIR/HLA interaction is most sensitive to substitution at peptide positions 7 and 8 of the HLA peptide binding groove, this being in agreement with the finding that the KIR binding site on the B27 molecule is located near the C-terminal residues 7 and 8 of the bound peptide. Peptides derived from microbial infections could be "arthritogenic". For instance, the EBV epitope bound to HLA*2705 fails to, or blocks, the binding of the inhibitory KIR3DL1 and this suggests that during infection, microbial peptides presented by HLA-B27 may be pro inflammatory by promoting the enhanced binding of the activating KIR3DS1, thereby increasing the pro-inflammatory effect through increased NK cell activation.

This is to be expected so there must be some reason the target cell is not killed by apoptosis and the inflammation is magnified by the continued survival of activated NK cells and some other T-cells.

It is known that KIR3DL2 expressing NK cells and CD4 T-cells are expanded in the peripheral blood of patients with B27-associated SpA’s. Strikingly up to 30% of memory effector CD4 T-cells (CD4 is a co-receptor for MHC Class II) in these patients peripheral blood express KIR3DL2 with a phenotype (CD28-(CD28 is supposedly present on all T cells)), CCR7-, CD45RO+) and are activated, expressing CD38 suggesting encounter with antigen. The KIR3DL2 expressing NK cells express perforin and are CD38+ suggesting recent activation.

Some authors contend that infection stimulates the production of cell surface B27 dimers by antigen presenting cells, either by direct mobilisation from an intracellular pool or, more probably, indirectly, from recycling unstable beta2m-associated heterotrimers. Binding of B27-dimers to KIR and LIR could then promote inflammation by enhancing the survival of proinflammatory KIR-expressing NK and T-cells or influencing the differentiation of LIR expressing antigen presenting cells.

KIR and Psoriatic Arthritis

Psoriatic arthritis (PsA) is an inflammatory skin disease classified among the HLA-B27-associated spondylarthropathies. Both genetic and environmental factors are at play. Genetic factors are important in terms of susceptibility and of disease progression and HLA-Cw6 is now considered to be the true psoriasis gene. Some studies have suggested that susceptibility to PsA is determined by the overall balance between activating and inhibitory KIR genes and their interaction with HLA-C genotypes. HLA-C1 allotypes are ligands for the inhibitory receptors KIR2DL2 and KIR2DL3 and the activating receptor KIR2DS2, whereas HLA-C2 allotypes are ligands for KIR2DL1 and KIR2DS1.
Absence of ligands for inhibitory KIR’s could potentially cause the lack of an inhibitory signal and subjects who carry these variants might show a lower threshold for NK (and/or T) cell activation and consequently an increase in their cytolytic activity through activating receptors which would contribute to the pathogenesis of PsA.

I read this as sort of Confirming Dr Browns work in Australia. He states that a loss of function in a varient of IL 23 (I think) allows the inflammation to continue unchecked as that part of the immune system that counters inflammation is not functioning correctly. Thus inflammation continues long after the triggering bacteria is gone from the system.

Is that how you take this as well David?

Hi drizzit

I hadn't read it that way but I can see that KIR receptors as well as IL23 receptors are present on Natural Killer cells (NK) and that patients with AS have alleles of KIR and alleles of IL23R that tend to promote the activation of NK and thus promote tissue destruction and inflammation.

The role of NK cells is to identify foreign substances and defend the body against infection and disease. It is known that up to 70% of AS patients have subclinical ileal inflammation resembling Crohn’s and that about 10% of AS patients have clinical IBD. The strong association with susceptibility to disease suggests that IL23/IL23R targeted therapies may even be capable of disease prevention. Some researchers believe that the role of IL23R in triggering inflammation in the intestinal wall may underlie its connection with Crohn’s (and possibly with AS).

This paper avoids talking about where the initiating "infection" is taking place, presumably in the gut - but against what? And why does the auto-inflammatory disease then target fibro-cartilage of the skeleton? Is there a specific microbe triggering the disease or is the gut lining inflammation triggered non-specifically.

That is the point Dr Brown made as well. That IL 23 therapy may totally prevent AS symptoms. Gee and there is an IL 23 drug already on the market

and we can't get to it yet unless you have psoriasis or $$$.

Hi drizzit

I have psoriasis - lucky me!
Do you know the name of the Anti-IL23 drug and who is he maker?
Is it's cost similar to other biologics?

Regards David

It is called Stelara. It blocks both the IL12p40 and IL23p40 cytokines

It has been out about a year now and had a very good safety record in the trials. In fact they did not even see an increase in infections like the TNF drugs.

http://www.prdomain.com/companies/J/Johnson&Johnson/newsreleases/2008121665639.htm

I It is one shot every three months I think and about the costs of the TNF drugs.

let me know if your try it as that is the one I would like to try but have to wait for the chrons trials and approva lol

Interesting, I knew the IL-23 drug was in trials, but hadn't realized it had been released, or limited to people with Psoriasis.

Thanks!

Warm hugs,