Where Innate Immunity and Autoimmune Disease Intersect

In this article, we discuss the possibility of innate lymphocytes as therapeutic targets in rheumatic disease as described in Nature Reviews Rheumatology.

Immunity is a complicated concept.  There are many players in an intricate game characterized by balance in the healthy person such that the body maintains its passive defenses while at the same time it’s ready to adapt and eradicate new threats.

Immunity cells can be classified as myeloid or lymphoid and may serve innate or adaptive roles.  T and B cells represent the lymphocytic adaptive defense and have the ability to change their receptor molecules in an effort to recognize a limitless variety of threats. Unlike the adaptive immune cells, innate cells cannot rearrange their coating but are well suited to defeating common pathogens. It is the identification of self vs. non-self that marks the line between self-defense, and self-destruction.

The concept of self seems easy to fathom.  However, today there are many organisms that disguise themselves as self and even droves of essential and non-pathologic bacteria that live in all of us that can become opportunistic under the right circumstances. Finally, even the self can be mistaken for an outside attacker stimulating an attack on the host by his or her own defenses:  Autoimmunity.  In any case the result is an inflammatory response that is either regulated and directed at killing a pathogen, or allowed to run unchecked harming the host. 

Two broad groups of innate lymphocytes were described in a review published in the Sept. 2 issue of Nature Reviews Rheumatology. The first group is characterized by their inability to rearrange receptors and includes natural killer cells (NK), innate-like B cells (ILB), and other subsets of innate lymphoid cells (ILCs).  The second group of ILCs are unconventional T cells. These T cells have the ability to change their T cell receptors. Both subsets have characteristics that allow them to produce a robust response to common pathogens. Unlike adaptive cells, which live in lymphoid organs, ILCs can enter tissues and produce large amounts of cytokines there. It is because of this ability to enter specific tissues that ILCs are able to play a role in tissue specific autoimmune diseases.

NK cells act as a first line of defense. They are either directly cytotoxic or produce pro-inflammatory cytokines which stimulate other cells to kill invaders. NK cells have a crucial ability, know by the missing-self hypothesis. Cancer cells and cells infected with viruses don’t display self-antigens but can be recognized by NK cells as missing the self-antigen. Although the role of NK cells in autoimmunity is unclear, they have been found in the joints of patients with rheumatoid arthritis (RA).

Other ILC subsets may have similar roles in autoimmune disease. Implicated in inflammatory bowel disease, these ILCs produce cytokines that may also contribute to asthma and general allergies. It is important to recognize that these ILCs also play vital roles in maintaining homeostasis, so targeting them in autoimmune therapy may produce serious side effects.

Natural killer T cells (NKT) have characteristics of both NK and T cells and are active in anti-tumor and antiviral responses in humans. NKT cells appear to have a protective role in autoimmune disease. This is evident in the observed reductions of NKT cells seen in patients with RA, SLE, systemic sclerosis and Sjogren’s syndrome. This effect is not related to glucocorticoid treatment. The protective effect of NKT cells has not been studied rigorously and there exists evidence that suggests that they also produce pro-inflammatory cytokines as well. Î¥ δT cells have a similarly ambiguous role in autoimmunity while mucosal associated invariant T cells (MAIT) appear to be solely pro-inflammatory. 

Although typically described as adaptive cells, some innate lymphoid B cell (ILB) subsets exist.  These subsets include:  B1 cells, marginal zone B cells, B10 cells and innate response activator B cells (IRA).  Unlike most B cells, these innate cells cannot undergo extensive molecular rearrangement. These cells produce natural IgM, which may act as a first line against bacterial infections.  These cells are mentioned here because B1 and B10 cells have been implicated in SLE.  As with the other ILC’s, ILB cell roles in autoimmunity have yet to be clarified. 

While it is as of yet unclear as to how the myriad of new rheumatologic therapies affect the ILC populations, initial investigation suggests that monitoring the activity and numbers of ILCs may be able to predict patient responses to different biologic drugs. Pro-inflammatory mediators released by ILCs contribute to autoimmune disease and have seen dramatic results with TNF targeting biologic therapies. Success with anti-TNF therapy is paving the way for therapeutic agents that target a wide variety of interleukins in an effort to make more headway in the fight against autoimmune diseases. At the heart of these efforts are the complicated and often ambiguous roles of ILC’s.  ILC’s are essential cells that we could not survive without. It is very important while examining them as potential bad actors in autoimmune disease, that physicians consider the consequences of targeting them in autoimmune therapy. The risk of infection is already real with current biologic treatments for rheumatologic disease. 

This review published in Nature Reviews Rheumatology should serve as a primer for speaking the same language where innate immunity and autoimmune disease intersect. The delicate balance between protective inflammation and self-destruction requires more examination but there is no doubt that innate lymphocytes play a role.


  • Innate lymphocytes (ILCs) are responsible for recognition of common pathogens and the inflammatory response to them.
  • ILCs differ from adaptive lymphocytes in their relative inability to alter their receptors to recognize specific or novel antigens.
  • ILC’s posses both pro-inflammatory and inflammatory subsets that may both exacerbate and or mitigate autoimmune disease.
  • While implicated in autoimmune disease, the specific roles and significance of ILCs remains to be determined.
  • Whether as targets for future therapies or markers for the success of biologic treatments, ILCs and their cytokines show promise for the future of autoimmune therapeutics.








Mark A. Exley, George C. Tsokos, et al. "What rheumatologists need to know about innate lymphocytes," Nature Reviews Rheumatology. Sept. 2, 2016. doi:10.1038/nrrheum.2016.140

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