# Understanding the Origins of Self-Attacking B Cells in Lupus
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Chapter 1: The Role of B Cells in the Immune System
B cells play a crucial role in our immune defense, acting as sentinels against pathogens like the influenza virus (H1N1) and COVID-19. However, when not properly regulated, these cells can become harmful, leading to autoimmune diseases such as Systemic Lupus Erythematosus (SLE).
B cells are responsible for producing antibodies, which are specific to each B cell and designed to identify and neutralize pathogens. Under normal circumstances, these cells learn to tolerate the body's own components to avoid attacking healthy tissues.
In SLE, this learning process fails, resulting in B cells that indiscriminately target the body's own proteins. This misdirected attack can manifest as symptoms including fever, fatigue, joint pain, skin rashes (like the characteristic butterfly rash), and kidney complications. SLE flares represent periods of intensified symptoms.
Where do these harmful B cells originate, and how do they contribute to the exacerbation of SLE?
Now, let’s delve deeper into research conducted by Tipton and colleagues from Emory University, who focused on the B cells of SLE patients undergoing flares. They employed advanced methodologies to analyze the antibody sequences of these B cells and compared them to those from healthy individuals vaccinated against influenza or tetanus.
Their findings, published in the esteemed journal Nature in 2015, titled “Diversity, cellular origin and autoreactivity of antibody-secreting cell expansions in acute Systemic Lupus Erythematosus,” revealed some striking similarities.
This video discusses autoimmune diseases and B cell immunity, featuring insights from Dr. Mark Shlomchik.
Section 1.1: The Study Findings
The 2015 study uncovered a staggering 40-fold increase in circulating B cells in the blood of SLE patients. This surge mirrors the immune response seen in healthy individuals who have received vaccinations.
Under typical circumstances, B cells in the lymph nodes undergo a selection process following an infection or vaccination. They are exposed to antigens—proteins that act as targets for pathogens. If the antibody on a B cell binds to an antigen, that B cell is chosen for further action. Selected B cells proliferate and migrate to the infection site, transforming into short-lived plasmablasts.
However, not every selected B cell becomes a plasmablast. A specific group of B cells undergoes a more extended maturation process, enhancing their antibody production's specificity and affinity. This process involves multiple mutations in the antibody's binding region, allowing it to fit the target antigen more precisely. Additionally, a rigorous selection phase eliminates any autoreactive B cells that might attack the body’s own tissues.
Following this maturation, these B cells develop into either memory B cells or long-lived plasma cells, providing enduring immunity against specific pathogens. If the same pathogen resurfaces, memory cells can quickly mobilize and mount an immune response, improving efficiency and reducing response time.
The researchers also noted a variety of B cells capable of binding to diverse antigens, with some populations more prevalent than others, and observed mutations in certain B cells' antibodies.
These observations suggest that SLE flare-ups share characteristics with the immune responses triggered by vaccinations, involving B cells that undergo selection, expansion, and antibody mutation.
Subsection 1.1.1: The Distinction: B Cells in SLE
While B cells in SLE patients follow a process similar to protective immune responses, they exhibit heightened activity. Notably, a specific subset of these B cells is more likely to proliferate and enter circulation.
“Our results indicate that circulating SLE antibody-secreting cells (ASCs) display enhanced responses to infectious antigens as well as typical SLE autoantibodies,” the authors noted. Surprisingly, “despite the lack of recent immunization or likely natural exposure, flu- and tetanus-specific cells were significantly increased among SLE ASCs, contrasting with negligible frequencies in healthy controls.”
Moreover, a considerable proportion of these B cells carry the VH4–34 gene, known for producing autoreactive antibodies, particularly the 9G4 antibody closely associated with SLE. The researchers observed that these cells “contributed significantly to clonal expansions in all five patients,” while such expansions were noted in only two out of eight vaccinated healthy controls. The authors emphasize that their findings “demonstrate a preferential expansion of VH4–34 ASCs in flaring SLE.”
So, where do these autoreactive B cells originate?
Chapter 2: Tracing the Autoreactive B Cells
To uncover their origins, Tipton et al. isolated and analyzed 9G4 ASCs from another SLE patient they had previously studied. They found that approximately one-third of the cells exhibited gene sequences similar to the identified VH4–34 ASCs, with 4.5% showing identical sequences.
They then engineered artificial antibodies based on the sequence of the 9G4 antibodies present during the flare. Their analysis revealed that “9G4 ASC antibodies exhibited substantial autoreactivity, including ANA, anti-dsDNA, anti-chromatin, anti-Ro, and anti-ribosomal P autoreactivity.” They also noted that some antibodies displayed significant auto-polyreactivity, meaning they could bind to multiple antigens, including those specific to SLE.
The researchers traced these cells back to primarily naive B cells—newly formed B cells that have yet to encounter antigens. “The common ancestor for several of the largest ASC clones could be identified in naive B cells present in circulation,” the authors reported. “A substantial contribution of naive cells to ASCs, including larger clones, was also identified in SLE for the predominant VH4–34.”
In essence, many ASCs derive from naive B cells, particularly those with the VH4–34 gene, which appear to bypass the usual training and selection processes typical during an immune response.
This video explores new therapy targeting autoreactive B cells in autoimmune diseases, presented by Johns Hopkins Rheumatology.
Section 2.1: SLE and Viral Infections
SLE flares can often be triggered by various factors, including sunlight, and previous studies have indicated that viral infections can exacerbate SLE symptoms. Notably, a 2019 study found that B cells expressing the VH4–34 gene are hyper-responsive to TLR7.
TLR7, or Toll-like receptor 7, is a type of protein that detects invading pathogens, such as the virus causing COVID-19, and activates the immune response. The connection between TLRs and the immune response to viruses has been discussed in other contexts.
This suggests that during an infection, when TLRs recognize microbes and initiate an immune response, the subset of B cells carrying the VH4–34 gene, which produce 9G4 antibodies, are more likely to be selected for expansion and circulation. When these autoreactive cells reach sufficient levels, they can cause significant damage, leading to SLE flares.
Given the relationship between the microbe-sensing TLR and the B cell response in SLE, it’s not surprising that viral infections can sometimes induce SLE-like symptoms or trigger flares.
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