Inflammation: A Driving Force of Autoimmune Disease

An abnormal inflammatory response is involved in the majority of acute and chronic conditions, with strong evidence linking chronic inflammation to the pathogenesis of autoimmune disease [1,2,3] . This includes multiple sclerosis, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, psoriasis, and idiopathic pulmonary fibrosis.

Major questions remain as to exactly how the immune cells and molecules that promote inflammation contribute to the pathogenesis of autoimmune diseases. [2]

While many treatments for these diseases rely on decreasing inflammation, they do not work for all patients and can have serious side effects, such as increasing the risk of infection [4]. Could a more precise understanding of the inflammatory mechanisms behind the broad range of autoimmune conditions pave the way for better therapies?

Around 150 years ago, research on multiple sclerosis cast doubt on the reputation of inflammation. The inflammatory response had long been viewed as an important component of the body’s defense against infection and a healing mechanism for damaged tissue [5]. But when a French neurologist reported the presence of inflammation in areas of multiple sclerosis lesions in the central nervous system, the evidence suggested it might actually cause harm.

This idea was reinforced in the 1980s when a team of British scientists found a slew of inflammation-inducing molecules called cytokines in the joints of patients suffering from rheumatoid arthritis [6]. The group went on to make a convincing case that inflammation was a driver, not a bystander, of disease. They showed that antibodies that blocked one type of cytokines – TNF alpha – dampened other cytokine levels in the joint tissues growing in the lab, and provided patients in clinical trials with almost immediate symptom relief. The work led to the development of infliximab (Remicade) as a targeted therapy for rheumatoid arthritis, as well as ulcerative colitis, psoriasis, and other autoimmune diseases.

Considering its relationship with autoimmune disease – and so many other diseases – inflammation can seem like the bad guy. However, inflammation held a good reputation for many millennia, dating back to ancient Egypt and Greece [5]. Acute inflammation protects the body and helps it recover from bacterial and viral infections, as well as toxins and physical injury [7]. Innate immune cells, which are the body’s first line of defense, rush to the area of injury [7]. During this delivery process, blood vessels dilate and leak—resulting in redness, heat, swelling, and pain commonly associated with inflammation.

This cascade is triggered by an interaction between innate immune cells and the insulting agent. Bacteria and viruses have distinct proteins, nucleic acids, and other molecules on their surface called pathogen-associated molecular patterns (PAMPs) that are recognized by receptors on the surface of innate immune cells, including neutrophils and macrophages [8,7,9]. If there is physical or chemical damage to tissues, cells release damage-associated molecular patterns (DAMPs) that immune cell receptors can also bind to [7].

Innate immune cells then spring into action, producing inflammatory cytokines and other molecules that recruit more immune cells that have a range of functions, including killing and clearing diseased cells from the area [8,10,11]. Cytokines can also pass through the blood-brain barrier and cause so-called sickness behavior – including sadness, fatigue, and reduced appetite – which also aids the body to heal by conserving energy [12,7].

Problems arise when inflammation lingers for more than a few days or weeks.

Some of the same processes that jumpstart acute inflammation – such as the interplay between DAMPs and innate immune cells – can also incite chronic inflammation. In this case, cells release DAMPs because of ongoing changes or stress, which can be the result of chronic infections, obesity, poor diet, exposure to toxins, and the aging process [7].

Moreover, adaptive immune cells such as T cells often arrive at the area of injury at higher levels during chronic inflammation than during an acute response [9]. While these cells contribute to the development of immune memory, they also release inflammatory cytokines that communicate with innate immune cells and provoke further inflammation [13].

For inflammation to become chronic, it not only has to be present in the body but also has to fail to stop producing these inflammatory cytokines [14]. There is a highly coordinated series of checks that limit the strength and duration of the acute inflammatory response [15]. As cytokines flood an area of injury, cells in the vicinity release lipoxin, a molecule that puts the brakes on this flood [16,15,17,18]. Later, innate immune cells produce a molecule called protectin that helps speed the resolution of the inflammatory response [19,20]. However, the de-escalation of inflammation can go awry in a variety of ways, such as genetic factors that lead to an exaggerated immune response or prolonged exposure to the inflammatory trigger [17]. 

Research over the last decade has pointed to the innate immune system as playing a key role in the creation and progression of autoimmune disease [4]. While T and B lymphocytes have long been blamed, there is growing evidence that innate immune cells are the force behind damage to adaptive immune cells [21].

Taking a look at rheumatoid arthritis, we see that neutrophils swarm affected joints and damage the surrounding tissue [22]. These innate immune cells also produce molecules that spur B cells to produce autoantibodies, a key component in the destructive nature of many autoimmune diseases. As part of the acute immune response, dendritic cells follow neutrophils to the affected joints, orchestrating a T-cell response [22].

These dendritic cells direct T cells to either promote further inflammation and become autoreactive, or toward a state of tolerance in which adaptive immune cells do not react to self-antigen. When joints are inflamed, dendritic cells follow the first path by pushing T cells toward autoreactivity and greater inflammation. However, major questions remain as to the exact factors, likely genetic and environment, underlying the abnormal innate immune response in rheumatoid arthritis [22].

The pathology of other autoimmune diseases experience the same level of complexity. In psoriasis, the involvement of T cells has long been clear, as well as the role that dendritic cells play to steer them toward an inflammatory state [23]. The interface between autoreactive T cells – which are thought to recognize self-antigens in the skin – and autoantibodies, contributes to the progression of psoriasis [23].  

In the past, adaptive immune cells – namely autoantibodies and autoreactive T cells – were thought to play a solo role in the development of systemic lupus erythematosus (SLE). Over the last decade, research studies have pinpointed how disruptions in the normal function of macrophages in SLE can delay the clearance of self-antigens (autoantibody targets) from tissue, which in turn could promote the production of autoantibodies and T cell malfunction [21].

The advent of infliximab and similar drugs that target TNF alpha cytokines was a game changer for treating autoimmune disease [4]. That being said, there is a subset of patients with rheumatoid arthritis, psoriasis, Crohn’s disease, and other conditions that do not respond to TNF inhibitors [4]. A growing number of therapies that inhibit other inflammatory cytokines have been developed to effectively combat the effects of psoriasis; others are being tested with autoimmune diseases such as SLE and Crohn’s disease [4].

Understanding the role of adaptive immune cells in autoimmune conditions has given way to several treatments based on inhibiting B or T cells. Rituximab, an antibody that depletes B cells, is a success story for relapsing multiple sclerosis [4]. Similarly, abatacept, a T cell inhibitor, is approved to treat rheumatoid arthritis and juvenile idiopathic arthritis [4].

The growing recognition of the role of innate immune cells in autoimmune disease has paved the way for new treatments. In the case of rheumatoid arthritis, drugs that block neutrophil products and dendritic cells showed the potential to repair tissue damage and reduce symptoms in mouse studies [22]. Likewise, mouse studies suggest that depleting harmful dendritic cells, or modifying the function of these cells, could have therapeutic benefits for SLE.

An upside of the long, entangled list of immune cell players and molecules that are involved in inflammation and autoimmunity is that there are ample targets to explore for new therapies [21].