Aberrant TNF Activity

Introduction:

Tumor necrosis factor is also called TNF or TNF-alpha. It is an important signaling molecule for immunity and immune regulation. Further, it is involved in cell growth, differentiation, survival, and death. Hence, the inappropriate secretion of TNF can be dangerous and lead to diseases.

What Are the Functions of TNF?

The following are the functions performed by TNF:

• During fetal life, TNF is involved in brain development.

• In an inflammation site, TNF actively engages neutrophils, macrophages, mast cells, and B cells. Hence, TNF is a mediator of both acute and chronic inflammation.

• It generates specific immune responses to a variety of causative organisms. For example, it recruits natural killer cells and T-cells against tumors, viruses, and certain bacteria.

• It plays an essential part in cell metabolism through various pathways.

What Are the Pathways Through Which TNF Works?

TNF operates through two receptors; tumor necrosis factor receptor 1 (TNRF 1) and tumor necrosis factor receptor 2 (TNRF 2). TNRF 1 is related to the cell inflammation and death pathway. However, TNRF 2 plays a pivotal role in cell proliferation, adhesion, migration, and survival.

What Are the Diseases Caused by Aberrant TNF Activity?

The action of TNF through TNRF 1 and TNRF 2 is called TNF signaling. Various lifestyle and autoimmune diseases are related to the TNRF 2 gene polymorphism (occurring in multiple forms). There are many diseases in which abnormal TNF activity is known.

1. Lifestyle Diseases:

• Obesity: It is the deposition of excessive fat in the body. Obesity is linked to poor lifestyle choices. TNF is associated with obesity due to the overexpression of TNF in fat cells.

• Diabetes Mellitus: It is an endocrine disorder. The relationship between TNF and Type II Diabetes mellitus has been studied. TNF is involved in the inhibition of an important pathway in insulin metabolism. Also, TNF inhibits glucose uptake in fat and muscle cells, thus exhibiting an important role in glucose metabolism.

• Cardiovascular Diseases: They are one of the conditions causing increased deaths worldwide. There is sufficient evidence that suggests that TNF regulates heart activity. Cardiovascular diseases such as coronary artery disease, congestive heart failure, atherosclerosis, and myocardial infarction are connected to the over activity of TNF. Hence, TNF has a role in heart disease progression.

2. Rheumatoid Arthritis: Rheumatoid arthritis (RA) is a rare auto-inflammatory disease affecting young individuals. Females are more affected. It is a chronic disorder involving small joints. An auto-immune response is generated due to abnormal immune regulation. Macrophages and monocytes are stimulated, which induces pro-inflammatory cells such as interleukin-1 and 6 (IL-1 and IL-6). Recruitment of osteoclasts (resorptive bone cells) also takes place. The result is inflammation of joints, cartilage damage, joint swelling, bone erosions, and a limited range of motion. This ultimately accelerates joint erosion and destruction.

3. Psoriatic Arthritis: Psoriatic arthritis (PsA) is a chronic disorder comprising skin, joints, and nail involvement. TNF plays a crucial role in the pathogenesis along with genetic and environmental factors. TNF activates macrophages and dendritic cells (a type of immune cell), skin cells, and T cells. Hence, it leads to skin and nail changes, bone erosion, and damage.

4. Inflammatory Bowel Disease: Inflammatory bowel disease or IBD is a broad term for the two autoimmune diseases depending upon their location in the gut. For example, Crohn’s disease (CD) affects the small and large intestines, mouth, esophagus, stomach, and anus, while ulcerative colitis (UC) predominantly affects the large intestine. TNF, along with IL-1, IL-6, and IL-7, is secreted by T-cells in the intestines. It eventually leads to mucosal inflammation, disruption, and blood vessel damage, leading to ulceration and bleeding.

5. Psoriasis: It is a skin disease with genetic and auto-immune causes. It presents with white scaly plaques on the skin with itching. Psoriasis occurs mainly on the extremities. TNF is involved in the overexpression of skin cells. Therefore, serum and skin lesions of the psoriatic patients have shown elevated levels of TNF.

6. Ankylosing Spondylitis: Ankylosing spondylitis (AS) mainly affects young men between the age of 20 to 30 years. It affects the bones of the head, neck, back, and chest. Patients suffer from bony fusions leading to immobility, pain, and loss of function. TNF mediates inflammation, bone erosion, and new bone formation in AS.

7. Non-infectious Uveitis: Non-infectious uveitis or NIU is the inflammation of the middle layer of the eye, i.e., uvea. Overproduction of TNF from macrophages leads to the recruitment of monocytes, lymphocytes, and neutrophils in the eye. Resultant inflammation destroys the uvea and leads to eye swelling.

Other than the list given above, TNF is also associated with neurological disorders such as Alzheimer’s disease and dementia, septic shock, and lung and kidney disorders.

What Are the Drugs Used Against Aberrant TNF?

TNF inhibitors are used as a treatment for disorders caused due to aberrant TNF activity. All the FDA-approved anti-TNF drugs are explained below.

• Infliximab: It is a monoclonal antibody used to treat IBD, AS, PsA, RA, and psoriasis. Infliximab works by blocking the binding of TNF with the receptors leading to an anti-inflammatory response. The half-life is approximately ten days, sustained by dose administration every eight weeks.

• Etanercept: Etanercept is a combination protein drug against RA, PsA, AS, and psoriasis. Etanercept is particularly effective in RA as it relieves the symptoms and stops progression. It is given as a subcutaneous injection and has a half-life of about three to four days.

• Adalimumab: It is used in patients allergic to Infliximab. It is given via subcutaneous injection and has a longer half-life of about 13 days. Hence, it requires less frequent doses. Adalimumab has been approved for managing RA, PsA, psoriasis, AS, and uveitis.

• Certolizumab: It is a newer anti-TNF drug approved by the FDA in 2018 for RA, CD, AS, PsA, and psoriasis. It has a higher efficacy than the other anti-TNF drugs and a half-life of two weeks resulting in a higher concentration.

• Golimumab: Golimumab has a higher affinity and is stronger than Infliximab and Adalimumab. The half-life is about twenty days. It is approved for treating RA, UC, PsA, and AS.

• Newer Anti-TNF Agents: Ozoralizumab is a monoclonal antibody under phase III clinical trial. It is smaller, more potent, and well-tolerated than the others. In addition, ZINC09609430 has been formulated to act specifically against TNF. However, it is still under safety and efficacy evaluation. Finally, CP-690334-01 is another treatment molecule undergoing trial.

What Are the Side Effects of Anti-TNF Drugs?

Common adverse effects of anti-TNF agents are bacterial, viral, and fungal infections, risk of lymphomas, congestive heart failure, and skin reactions. Moreover, anti-TNF agents should be given to pregnant women only after the risk-benefit ratio is properly assessed.

Conclusion:

TNF contributes to the induction and progression of many diseases. Targeting TNF receptors has proven to be very effective in treating such diseases. Hence, further research on TNF signaling pathways can facilitate improvement in disease management.