Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus, 2008, Schepis et al

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Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus

Spoiler: Authors

Schepis, Danika; Gunnarsson, Iva; Eloranta, Maija‐Leena; Lampa, Jon; Jacobson, Stefan H.; Kärre, Klas; Berg, Louise

Abstract
Summary
Natural killer (NK) cells belong to the innate immune system but can also affect adaptive immune reactions. This immune regulatory function is often ascribed to the CD56bright subpopulation of NK cells that is prevalent in secondary lymphoid tissues and has potent cytokine‐producing ability.

The NK cells have been described as affecting autoimmune disease and stimulating B‐cell production of antibodies, but their role in systemic lupus erythematosus (SLE) pathology has not been extensively studied.

We have studied NK cells in SLE, a B‐cell‐driven systemic autoimmune disease, and phenotypically characterized peripheral blood NK cells in comparison to NK cells from patients with immunoglobulin A nephritis, rheumatoid arthritis and healthy individuals. We have found an increased proportion of CD56bright NK cells in SLE, regardless of disease activity.

We detected a somewhat increased expression of the activating receptor NKp46/CD335 on NK cells from SLE patients, although neither the percentage of NK cells of all lymphocytes nor the expression of other NK receptors analysed (LIR‐1/CD85j, CD94, NKG2C/CD159c, NKG2D/CD314, NKp30/CD337, NKp44/CD336, CD69) differed between patient groups.

We show that type I interferon, a proinflammatory cytokine known to be abundant in SLE, can cause increases of CD56bright NK cells in vitro. We confirmed that serum levels of interferon‐α were increased in active, but not in inactive, disease in the SLE patient group.

In conclusion, we found an increased proportion of CD56bright NK cells in the blood of SLE patients, although it remains to be examined whether and how this relates to the disease process.

Web | DOI | PMC | PDF | Immunology

 

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Also this from the Introduction

There are two major subpopulations of human NK cells, the CD56dim NK cells, which express killer immunoglobulin-like receptors (KIR) and CD16 (FcγRIIIa), and the CD56bright NK cells which lack expression of KIR and CD16 and which express the high-affinity interleukin-2 (IL-2) receptor α subunit CD25. These two sets of human NK cells differ in their function and distribution. The CD56dim NK cells make up approximately 90% of blood NK cells and have a high cytolytic capacity, while the CD56bright NK cell is the main NK cell type found in secondary lymphoid tissue and at sites of inflammation. It is conceivable that CD56bright NK cells may affect autoimmune diseases by promoting T-cell activation in lymphoid tissues5 and subsequently B-cell responses. It is also possible that NK cells may play a more direct role in promoting B-cell responses during SLE, in part through CD40/CD154 interactions between these cell types

We found an increase in the proportion of CD56bright NK cells in patients with SLE regardless of disease activity. Furthermore, type I IFN could induce increased proportions of CD56brightNK cells in vitro. Levels of IFN-α were elevated in the patients with SLE in our study, although only in those with active disease.

Not sure what it all means! Wiser minds may want to chip in. But I found the different types of NK cells and the tissues they lurk in interesting. There’s also some papers on their potential role in neurological conditions.

 

[jnmaciuch]

Not sure what it all means! Wiser minds may want to chip in. But I found the different types of NK cells and the tissues they lurk in interesting. There’s also some papers on their potential role in neurological conditions.

Very interesting find! It could be relevant to the dara study since the only type of NKs they measured were CD56+CD16+, aka the "CD56dim" type described here. If there was some transient or organ-specific immune signaling in ME/CFS, this paper suggests that it would skew the proportion of NKs in the CD56bright vs. CD56dim categories. Which, if you're only measuring CD56+CD16+ NKs, would create the appearance of lower levels of NKs in participants with more of that signaling.

What's surprising about this study is that the NK subtype skewing was found regardless of whether participants had detectable levels of IFN-a in their blood. Which suggests that either 1) the NK cell subtype skewing is a long-lasting effect that can persist even without active signaling, or 2) that even in "inactive" lupus there is still active cytokine signaling hidden in lymphoid organs. From memory I don't think NK cells are particularly long lived (compared to other long-lived immune cell populations, at least). Though if someone has only been out of an active flare for a few weeks/months the NKs might have stuck around that long.

 

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While looking at CD38 involvement I also came across this paper which seems to indicate expression of CD38 is similar on both but bright have more of a regulatory role which is influenced by CD38 pathways.

I can’t access it unfortunately but from the abstract it looks like it could also be interesting, but I can’t quite get my head around it all or hold the pathways in my mind all at once…

CD56brightCD16− NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4+ T Cell Proliferation, 2015, Morandi et al

Spoiler: Authors

Morandi, Fabio; Horenstein, Alberto L; Chillemi, Antonella; Quarona, Valeria; Chiesa, Sabrina; Imperatori, Andrea; Zanellato, Silvia; Mortara, Lorenzo; Gattorno, Marco; Pistoia, Vito; Malavasi, Fabio

Abstract
Abstract
Recent studies suggested that human CD56brightCD16− NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotide-metabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO).

Peripheral blood CD56dimCD16+ and CD56brightCD16− NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56brightCD16− than in CD56dimCD16+ NK cells. CD57 was mostly expressed by CD56dimCD16+ NK cells. CD203a/PC-1 expression was restricted to CD56brightCD16− NK cells.

CD56brightCD16− NK cells produce ADO and inhibit autologous CD4+ T cell proliferation. Such inhibition was 1) reverted pretreating CD56brightCD16− NK cells with a CD38 inhibitor and 2) increased pretreating CD56brightCD16− NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration.

CD56brightCD16− NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4+ T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56brightCD16− NK cells isolated from inflammatory pleural effusions display a potent regulatory activity.

In conclusion, CD56brightCD16− NK cells act as “regulatory cells” through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases.

Web | DOI | PDF | The Journal of Immunology

 

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Which, if you're only measuring CD56+CD16+ NKs, would create the appearance of lower levels of NKs in participants with more of that signaling.

Ah, interesting. I wondered about different NK cell subtype populations but hadn’t twigged that.

From memory I don't think NK cells are particularly long lived (compared to other long-lived immune cell populations, at least). Though if someone has only been out of an active flare for a few weeks/months the NKs might have stuck around that long.

There seems to be some discussion of more long lived NK cells in some papers, particularly in certain tissues or in these ‘memory’ NK cells? I’m not sure how that compares to other long lived immune cell populations though. And some recirculation via lymph rather than blood, would that impact plasma measurements?

 

[jnmaciuch]

There seems to be some discussion of more long lived NK cells in some papers, particularly in certain tissues or in these ‘memory’ NK cells? I’m not sure how that compares to other long lived immune cell populations though. And some recirculation via lymph rather than blood, would that impact plasma measurements?

Yes there are some "memory" subtypes, though if my memory serves (ha) that's only going to be some fraction of NK cells. So it seems less likely to explain this paper's findings where the inactive lupus subset is nearly matching the active one.

cell type frequency in the lymph vs. blood are certainly not 1:1 but (barring some specific circumstances) they tend to at least echo each other.