The Complement system is a participant in many diseases such as paroxysmal nocturnal hemoglobinuria (PNH), hemolytic uremic syndrome (HUS), hereditary angioedema (HAE), etc. Among these rheumatic diseases, systemic lupus erythematosus (SLE) is proved to have the closest relationship with the complement system.

In 1896, Jules Bordet discovered the complement system, and related research earned him the Nobel Prize in Physiology in 1919. At that time, it happened that World War I caused the Nobel Prize to cease for four consecutive years. Jules Bordet became the first recipient of the Physiology Award after the re-award.

After this, complement-related research has experienced many developments and even subversions. Compared to Jules Bordet’s study back then, today’s understanding of complement system is beyond recognition. This article will discuss the relationship between complement and SLE.

Defects in the Complement System Lead to SLE

Congenital defects in the complement system make people more vulnerable to bacterial viruses. This is a major category of congenital immunodeficiency. Interestingly, this not only leads to a decline in resistance to pathogens, but also brings autoimmune diseases.

About 93% of C1q-deficient people will suffer from SLE. Similarly, 75% of those with C4 deficiency and over 30% of those with C2 defects also lead to SLE. Most of the C1r and C1s defecting will also result in SLE. However, due to their low prevalence, it is not appropriate to accurately determine the strength of their association. No stronger innate factors related to SLE have been found. Fortunately, the incidence of such birth defects is low.

Secondary Complement Deficiency and SLE

Bacterial infections, SLE, etc. will cause the level of complement to drop. SLE brings a lot of immune complexes, which combine with complement to cause damage to the body. This is particularly evident in lupus nephritis.

Except that the combination of immune complex and complement leads to the decrease of complement, there are also antibodies against complement. The most widely used is anti-C1q antibody. About 30% of patients with SLE have anti-C1q antibodies, and it is 68% of patients with lupus nephritis. Therefore, a positive anti-C1q antibody indicates a high possibility of lupus nephritis.

Complement-related Drugs and SLE Treatment

The complement system plays an important role in the pathogenesis of many diseases. The pharmaceutical industry has also developed many drugs in a targeted manner.

(1) Eculizumab

Eculizumab is a humanized monoclonal antibody. The antibody binds to complement component 5 and prevents it from cleaving into C5a and C5b, and C5b is necessary to form a membrane attack complex (MAC), which is an important link for complement to participate in body damage, so eculizumab can be used to treat PNH and HUS. However, it is a pity that the clinical practical significance has not been seen in the clinical drug experiments for the treatment of SLE.

(2) Avacopan

The latest major breakthrough in the rheumatology research is Avacopan, a small molecule compound that targets the complement C5a receptor.

Recent clinical randomized double-blind controlled trials have confirmed that Avacopan can successfully replace hormones in combination with other drugs. The biggest problem of this experiment is that the number of cases participating in the experiment is not enough, and the observation time is not long enough. Can Avacopan replace hormones during SLE treatment? There is no reliable clinical controlled trial to verify.

Clinical experience tells us that compared with SLE, ANCA-associated vasculitis tends to rely more on hormones. Since ANCA-associated vasculitis can get out of hormones during treatment, it is possible to look forward to hormone replacement during SLE treatment. The complement therapeutics might the hope of the hormonal-free era of lupus treatment.

Recently, in a study published in Cancer Research, scientists from New York University and other institutions have found that a key immune signal may play a previously unknown role in turning off the immune system to attack pancreatic cancer. The researchers found that the immune signaling protein interleukin 1β (IL-1β) can be made and released by pancreatic tumor cells, while it reduces the body’s anti-cancer immune response, thereby promoting the growth of pancreatic ductal adenocarcinoma (PDA), a type of cancer that is usually fatal within two years.

The researchers say blocking IL-1 Beta activity in mice with antibodies may reduce PDA tumor growth by 32%, while other experiments can combine anti-IL-1β antibodies (which can lock and neutralize their targets) with antibody therapies that have been approved to turn off the PD1 protein checkpoint. To protect normal cells from immune attack, the immune system uses checkpoints on immune cells to turn off when they receive normal signals; cancer cells intercept checkpoints to turn off the function of the immune system, triggering the immune knowledge of CD8 + T cells, which in turn kills cancer cells, a therapy called checkpoint inhibitors can effectively neutralize this effect.

Although effective against a variety of cancers, checkpoint inhibitors are helpless for the treatment of PDA. In some experiments, the tumor response rate to therapy is only about 3%, and poor CD8 + T cell infiltration and immunosuppression are the main reasons for the limitations. In the current study, the researchers found that adding anti-IL-1β antibody to anti-PD-1 antibody therapy doubled T cell infiltration into PDA and increased the anti-tumor activity of PD-1 blockers by 40%.

Dr. Dafna Bar-Sagi, a researcher, said that by engineering mice to lack the IL-1β gene, we found for the first time that pancreatic cancer cells can produce IL-1β, which is essential for the continued growth of PDA tumors, and blocking IL-1β using antibody therapy may provide a novel strategy to make pancreatic tumors on the host immune system, thus potentially increasing the therapeutic potential of checkpoint inhibitors.

The findings of this study are consistent with previous research work by other researchers, which describe that the body’s microbiome changes when PDA is present, and that the microbiome is a key factor in cancer growth, an area that traditionally allocates IL-1β production to immune cells, but this study found that pancreatic tumor cells can also respond to proteins released by specific bacteria. The researchers say bacterial products can activate a protein on the cell surface called toll-like receptors, which can turn on the chain reaction needed for IL-1β production in cancer cells.

In addition, the researchers found that high levels of IL-1β promoted increased production of high-density proteins such as collagen in nearby pancreatic stellate cells, an overgrowth of fibrous tissue that often occurs near pancreatic tumors and is not associated with treatment resistance. Active pancreatic stellate cells are able to induce the production of signaling proteins, which can attract macrophages into tumors and reprogram them to become M2 macrophages that can effectively inhibit immune responses; now researchers have confirmed that high levels of IL-1β and M2 macrophages and fibroblast-driven connective tissue formation may reduce the ability of CD8 + T cells that kill cancer cells to enter tumors.

Finally, researcher Shipra Das said, this study provides strong evidence that blocking IL-1β activity may promote better penetration of T cells into tumors and kill cancer cells, which may hopefully overcome the dilemmas and limitations of current immunotherapy in the treatment of pancreatic cancer.

The World Health Organization announced the global pandemic of COVID-19 in March 2020, the second pandemic in the 21st century. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA beta coronavirus of the Coronaviridae family. The expansion of virus populations, such as SARS-CoV-2, has accumulated many shared polymorphisms, which has caused confusion in traditional clustering methods. In this case, a method to reduce the complexity of the sequence space occupied by the SARS-CoV-2 population is necessary for accurate clustering.

Recently, researchers from the Federal University of Ubrantia, the Federal University of Visosa, and the University of Brasilia, Brazil, proposed to subdivide the global SARS-CoV-2 population into 16 well-defined subtypes by focusing on polymorphisms in widely shared nonstructural cistrons (nsp3, nsp4, nsp6, nsp12, nsp13, and nsp14), structural genes (spike proteins and nucleocapsid), and accessory genes (ORF8). The related research results were published on the preprint server bioRxiv, and the article title is “The global population of SARS-CoV-2 is composed of six major subtypes”.

The researchers found that the six virus subtypes dominate the patient population, but all 16 subtypes of viruses exhibit amino acid substitutions that may have phenotypic significance. The researchers speculate that the virus subtypes detected in this study are records of the early stages of SARS-CoV-2 diversification. These viruses are randomly sampled to form virus populations around the world, which is a typical founder effect.

The researchers said that the genetic structure of the virus identified by SARS-CoV-2 infected persons provides substantial guidance for maximizing the effectiveness of candidate vaccines or drug trials.

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