Your immune system is the network of cells and tissues throughout your body that work together to defend you from viruses, bacteria, and infection. It tries to identify, kill, and eliminate the invaders that might hurt you.

Parts of the immune system include:

• Acquired (or adaptive) immune system, which develops as you grow. Invaders provoke your body into producing antibodies so that your body “remembers” those invaders. Your body can then fight them if they come back.
• Innate (or inborn) immune system, which uses white blood cells instead of antibodies to destroy invaders.

Autoinflammatory diseases refer to problems with the innate immune system’s reactions. Immune cells target the body’s own healthy tissues by mistake, signaling the body to attack them. This can cause intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal buildup of a blood protein in vital organs.

The immune system is the complex collection of cells and organs that destroys or neutralizes pathogens that would otherwise cause disease or death. The lymphatic system, for most people, is associated with the immune system to such a degree that the two systems are virtually indistinguishable. The lymphatic system is the system of vessels, cells, and organs that carries excess fluids to the bloodstream and filters pathogens from the blood. The swelling of lymph nodes during an infection and the transport of lymphocytes via the lymphatic vessels are but two examples of the many connections between these critical organ systems.

Anatomy of the Lymphatic System

Lymphatic vessels in the arms and legs convey lymph to the larger lymphatic vessels in the torso.

Overview

The lymphatic system is a series of vessels, ducts, and trunks that remove interstitial fluid from the tissues and return it the blood. The lymphatics are also used to transport dietary lipids and cells of the immune system. Cells of the immune system all come from the hematopoietic system of the bone marrow. Primary lymphoid organs, the bone marrow and thymus gland, are the locations where lymphocytes of the adaptive immune system proliferate and mature. Secondary lymphoid organs are site in which mature lymphocytes congregate to mount immune responses. Many immune system cells use the lymphatic and circulatory systems for transport throughout the body to search for and then protect against pathogens.

Some examples of autoinflammatory disease and their symptoms include:

• Familial Mediterranean Fever (FMF), which causes recurring bouts of fever. Other symptoms include:
  • Severe abdominal pain due to inflammation of the stomach cavity (peritonitis).
  • Arthritis (painful, swollen joints).
  • Chest pain from inflammation of the lung cavity (pleurisy).
  • Skin rashes.
• Neonatal Onset Multisystem Inflammatory Disease (NOMID) affects the skin, joints, eyes, and central nervous system. For most children, the first sign of the disease is a rash that develops within the first six weeks of life. Other problems can follow, including:
  • Fever.
  • Meningitis.
  • Joint damage.
  • Vision loss.
  • Hearing loss.
  • Mental retardation.
• Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is associated with:
  • Long, dramatic, episodes of high fever.
  • Severe pain in the abdomen, chest, or joints.
  • Skin rash.
  • Inflammation in or around the eyes.
• Deficiency of the Interleukin-1 Receptor Antagonist (DIRA) can cause the following serious conditions in children:
  • Swelling of bone tissue.
  • Bone pain and deformity.
  • Inflammation of the layer of connective tissue around bone.
  • Skin rash that can cover most of the body.
• Behçet’s disease can cause the following symptoms:
  • Mouth or genital sores.
  • Redness and swelling in the eyes.
  • Arthritis.
  • Skin problems.
  • Swelling of the digestive system, brain, and spinal cord.
• Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE) can include the following symptoms, which generally develop during the first year of life:
  • Recurrent fevers.
  • Purpura.
  • Joint pain.
  • Contractures.
  • Developmental delay.
  • Facial changes, including a loss of fat on the face, and swollen lips and eyelids.

Autoinflammatory diseases are typically caused by changes in certain genes. This causes problems with proteins that are important in specific body functions. For some diseases, the cause is unknown.

Treatments for autoinflammatory diseases can involve medications that:

• Reduce inflammation.
• Suppress the immune system.

Researchers continue to explore the genetics and causes of autoinflammatory diseases. Understanding the causes of these diseases will improve both diagnosis and treatment.

Autoinflammatory diseases are caused by the immune system—the body’s disease defense that fights off viruses, bacteria, and infection—attacking your body by mistake. That can cause a fever, rash, muscle aches, joint and other tissue swelling, and organ problems.

Members of three families came to NIH’s Clinical Center with symptoms similar to those caused by an autoinflammatory disease, but with no known cause. The seven patients ranged from 10 to 82 years old. Their symptoms included fevers, swollen lymph nodes, severe abdominal pain, gastrointestinal problems, headaches and, in some cases, abnormally enlarged spleen and liver. Although their condition isn’t life-threatening, they can have persistent fever and swollen lymph nodes from childhood to old age, as well as other symptoms that can lead to lifelong pain and disability.

A team of researchers led by Dr. Daniel Kastner of NIH’s National Human Genome Research Institute (NHGRI) and Dr. John Silke at the Walter and Eliza Hall Institute in Australia carried out a study looking for the cause of the syndrome. After ruling out infections and cancer, they sought answers by genomic sequencing. The study, which was funded by several NIH components, was published on January 2, 2020, in Nature.

The team discovered only one gene—RIPK1—that was consistently different in all patients. Each of the three families had its own unique mutation affecting the very same DNA letter in the RIPK1 gene. Each affected person had one mutant and one normal copy of the gene, while unaffected family members had two normal copies.

The protein encoded by the RIPK1 gene is involved in inflammation and programmed cell death—the process by which old cells die so they can be replaced by new ones. Each of the patients’ mutations occur at the location where RIPK1 can be cleaved to prevent it from initiating inflammation and cell death. Thus, Kastner’s team named the disease cleavage-resistant RIPK1-induced autoinflammatory, or CRIA, syndrome.

Mouse embryos with two mutant copies of RIPK1 did not survive in the uterus due to excessive cell death signals. However, mice with one mutant copy and one normal copy, like the CRIA patients, were mostly normal but had heightened inflammatory responses.

The team tested therapies known to reduce inflammation in seven patients with CRIA syndrome. While drugs such as etanercept and anakinra, which are used to treat autoinflammatory and chronic diseases such as rheumatoid arthritis, had little effect, one drug called tocilizumab did. Tocilizumab is a drug that suppresses a specific signaling molecule in the immune system. It reduced the severity and frequency of CRIA syndrome symptoms in five out of the seven patients—in some cases with life-changing effects.

“This discovery underscores the tremendous power of combining astute clinical observation, state-of-the-art DNA sequencing, and the sharing of sequence data in large publicly-accessible databases,” Kastner says.

Researchers are now trying to understand the molecular mechanism that enables tocilizumab to treat CRIA syndrome. Specific inhibitors of RIPK1, which are under development, may also hold promise in both CRIA syndrome and other seemingly intractable inflammatory conditions.

Over the last 20 years, three families have been unsuspectingly linked by an unknown illness. Researchers at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, and other organizations have now identified the cause of the illness, a new disease called CRIA syndrome. The results were published in the journal Nature.

NHGRI scientific director Daniel Kastner, M.D., Ph.D., a pioneer in the field of autoinflammatory diseases, and his team discovered CRIA, which has symptoms including fevers, swollen lymph nodes, severe abdominal pain, gastrointestinal problems, headaches and, in some cases, abnormally enlarged spleen and liver.

The disorder has characteristics typical of an autoinflammatory disease, where the immune system appears to be activated without any apparent trigger. Although the condition is not life-threatening, patients have persistent fever and swollen lymph nodes from childhood to old age, as well as other symptoms that can lead to lifelong pain and disability.

When confronted by patients’ symptoms, who were first seen at the NIH Clinical Center, researchers looked for infections and cancer as the cause. After those were ruled out, they sought answers in the genome, a person’s complete set of DNA. Kastner and his team sequenced gene regions across the genome and discovered only one gene — RIPK1 — to be consistently different in all patients.

Researchers identified a specific type of variation in the patients: a single DNA letter at a specific location incorrectly changed. This change can alter the amino acid added to the encoded protein. These are called "missense" mutations.

Remarkably, each of the three families had its own unique missense mutation affecting the very same DNA letter in the RIPK1 gene. Each affected person had one mutant and one normal copy of the gene, while the unaffected family members had two normal copies of the gene.

The researchers also looked at 554 people with sporadic unexplained fever, swollen glands and other symptoms or diseases, and then at over a quarter million people from public sequence databases to see if they encountered the same RIPK1 mutations. When they did not find such mutations elsewhere, it was clear that they were onto something new.

"It was as if lightning had struck three times in the same place," said Kastner, who led the NHGRI team. "This discovery underscores the tremendous power of combining astute clinical observation, state-of-the-art DNA sequencing, and the sharing of sequence data in large publicly-accessible databases. We live in a very special time."

The RIPK1 gene encodes for the RIPK1 protein, which is involved in the body’s response to inflammation and programmed cell death. To make sure that RIPK1 action does not initiate inflammation and cell death in all cells, another protein “cuts” the RIPK1 protein at a specific location in the protein sequence. The research team noticed that all the mutations in CRIA patients occur at the location where RIPK1 usually gets cut, resulting in an uncuttable, seemingly indestructible RIPK1 protein.

This suggests that cutting RIPK1, thereby disarming it, is crucial to controlling cell death and inflammation. Recognizing this cause-effect relationship, Kastner’s team named the resulting disease cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome.

Although the researchers made the connection between CRIA syndrome and RIPK1 mutations, they still needed to understand the molecular mechanisms involved in the disease. To do this, Kastner and his team collaborated with Najoua Laloui, Ph.D., and John Silke, Ph.D., at the Walter and Eliza Hall Institute in Australia, who made specialized mouse models with similar RIPK1 mutations as seen in CRIA patients.

The Australian team discovered that mouse embryos with two mutant copies of RIPK1 (and no normal copy) did not survive in the uterus due to excessive cell death signals, which further confirmed the importance of cutting RIPK1 to limit its function in normal cells. However, mice bearing one mutant copy of RIPK1 and one normal copy, as is the case for CRIA patients, were mostly normal but had heightened responses to a variety of inflammatory stimuli, which the researchers think may suggest a possible mechanism for how the human disease occurs.

Kastner and his team worked to find a treatment for CRIA syndrome. Seven patients with the condition were given therapies that are known to reduce inflammation. While drugs such as etanercept and anakinra, which are routinely used to treat autoinflammatory and chronic diseases such as rheumatoid arthritis, had little effect on the patients, one biological drug called tocilizumab did. Tocilizumab, a drug that suppresses the immune system, reduced the severity and frequency of CRIA syndrome symptoms in five out of seven patients in some cases with life-changing effects.

Hirotsugu Oda, M.D., Ph.D., a post-doctoral researcher in Kastner’s laboratory and co-first author of the paper, said: "As a physician-scientist, the most thrilling experience to me was to hear the mother of a CRIA patient say that her son was a completely different, healthy child after the tocilizumab treatment. Through the genetic diagnosis, we were able to contribute to the treatment of a few patients. This is, after all, the ultimate goal."

Researchers are now trying to understand the detailed molecular mechanism that enables tocilizumab to treat CRIA. Specific inhibitors of RIPK1, which are under development, may also hold promise in both CRIA and other seemingly intractable inflammatory conditions.