The Role of Innate Lymphoid Cells in Inflammatory Rheumatic Disease

Innate lymphoid cells have a clear role in rheumatic disease and its related inflammatory process.

Mark Wenink and fellow researchers in the Netherlands present an update on the role of innate lymphoid cells in the pathogenesis of rheumatic disease, but also point out in a recent Arthritis & Rheumatology article that innate lymphoid cells play an important part in tissue homeostasis.

The balance between tissue homeostasis and inflammation and the role of innate lymphoid cells in both has been well demonstrated in skin and gut disease. However, descriptions of innate lymphoid cells contribution to rheumatic disease are lacking.

Innate Lymphoid Cells and T Cells

Although innate lymphoid cells and T cells share many characteristics, there are important differences.

T cells are primed by recognizing major histocompatibility complex II antigens presented by dendritic cells

Innate lymphoid cells do not express antigen receptors that recognize major histocompatibility complexes, but instead are activated by a wide range of chemical and molecular mediators.

T cells must be mobilized to the periphery to act at tissue barriers.

Innate lymphoid cells are always present and ready to be first responders in the immune response.

Natural killer cells are considered innate lymphoid cells, however, they are the only kind that directly induce cytotoxicity. Innate lymphoid cells that are not cytotoxic are called helper like cells.

Innate lymphoid cell development

By means of various transcription factors, helper like innate lymphoid cells develop from a common precursor cell line.

Human CD34+ cells give rise to innate lymphoid cells under specific conditions but much of the evidence concerning innate lymphoid cell development comes from animal models.

Innate lymphoid cell subsets

Classification of innate lymphoid cells is based on their developmental pathways.

1)            Innate lymphoid cells type 1 (ILC1s)

• Include natural killer cells, CD127 and CD103 innate lymphoid cell lines.
• They are found in intestinal mucosa, salivary glands, the liver and the female reproductive tract.
• Natural killer cells are present in the blood in greater numbers that other type 1 innate lymphoid cells.
• The role of type 1 innate lymphoid cells in protecting against infection is important but the authors state that overactive responses as well as insufficient ones my cause immunopathology.

2)            Innate lymphoid cells type 2 (ILC2s)

• Similar to T helper type 2 cells, which require GATA-3 transcription factor for development.
• They are found in the lung, skin and adipose tissue.
• They respond to various interleukins and other cytokines by producing allergic and fibrosis related mediators.
• Unlike other innate lymphoid cells, type 2 cells posses a prostaglandin D2 receptor which promotes the migration of type two innate lymphoid cells increasing their effect.
• Type 2 innate lymphoid cells promote immunity against extracellular parasites, induce tissue repair, and promote beige fat reducing insulin resistance.
• Type 2 innate lymphoid cells are implicated in general allergy, asthma and atopic dermatitis. 

3)            Innate lymphoid cells type 3 (ILC3s)

• The prototype type 3 innate lymphoid cell is a lymphoid tissue inducer.
• During development type 3 cells stimulate the formation of lymph nodes and Peyer’s patches.
• Certain type 3 innate lymphoid cells inhabit secondary lymphoid organs and mucosal tissues and protect the body’s barriers from translocation of intestinal organisms.
• Type 3 innate lymphoid cells are essential for gut homeostasis.

4)            Plasticity

• Innate lymphoid cells are able to switch types depending on the inflammatory condition.
• The type of interleukin that the lymphoid cell is exposed to determines whether it will change type and which type it will become.

Innate lymphoid cells: Psoriasis and inflammatory bowel disease

1)            Psoriasis

• Interleukin 22 and 17A cytokines produced by innate lymphoid cells play key roles in the development of psoriasis.
• Innate lymphoid cells appearing in the unaffected skin of psoriatic patients appears altered.

2)            Inflammatory bowel disease

• As mentioned before, innate lymphoid cells play an important part in gut homeostasis hence the subsequent pathologic antimicrobial state of inflammatory bowel disease that occurs when these cells become altered.
• In contrast to psoriasis, healthy gut is characterized by large numbers of type 3 innate lymphoid cells being present.
• Altered type 3 innate lymphoid cells secrete pro-inflammatory cytokines in inflammatory bowel disease patients.

The different functional properties of innate lymphoid cells in psoriasis versus inflammatory bowel disease highlights the fact that whether these cells are pathogenic or protective is highly dependent on the environment and tissue in which they are located.

Evidence of innate lymphoid cells in other rheumatic diseases

1)            Psoriatic arthritis

• Innate lymphoid cells were found in synovial fluid.
• There appear to be increased numbers of type 1 innate lymphoid cells present in psoriatic arthritis patients synovia.
• When compared to synovial fluid, circulating innate lymphoid cells were lower in psoriatic arthritis patients when compared to healthy people.

2)            Ankylosing spondylitis

• Innate cells similar to T cells produce tumor necrosis factor, interleukin 17 and 22, which drive the pathogenesis of ankylosing spondylitis.
• The gut microbiome may also play a part in the development of ankylosing spondylitis.

3)            Rheumatoid arthritis

• Innate lymphoid cells also found in synovial fluid however, compared with psoriatic arthritis, relatively few type 3 cells are present in the fluid.
• Innate lymphoid cells support antibody production by B cells.

4)            Sjogren’s syndrome

• Innate lymphoid cells have been identified in the saliva where interleukin 22 contributes to pathogenesis.

5)            Systemic lupus erythematosus

• There are increased numbers type 2 innate lymphoid cells in lupus patients.

6)            Scleroderma and Systemic Sclerosis

• Innate lymphoid cells are abundant in the skin and blood of scleroderma and systemic sclerosis patients.
• When fibrosis is present, type 2 innate lymphoid cells seem to be implicated.
• Type 1 innate lymphoid cells were found to produce tumor necrosis factor in the blood of patients with scleroderma and systemic sclerosis.

Take Home Points for Physicians

Innate lymphoid cells clearly play a role in rheumatic/inflammatory disease states.

Innate lymphoid cells also are essential to provide a normal state of tissue homeostasis.

The exact mechanisms by which innate lymphoid cells support inflammation are complicated and more research in humans is needed.

Understanding the role of innate lymphoid cells and ultimately targeting their development, plasticity and effector functions may lead to new therapies for patients.

References:

Mark H. Wenink, Emmerik F. A. Leijten, Tom Cupedo and Timothy R. D. J. Radstake. “Innate Lymphoid Cells Sparking Inflammatory Rheumatic Disease?”Arthritis & Rheumatology. Vol. 69, No. 5, May 2017, pp 885–897
DOI 10.1002/art.40068