Examining B-cell dynamics and responsiveness in different inflammatory milieus using an agent-based model

Abstract

Introduction: B-cells are essential components of the immune system that neutralize infectious agents through the generation of antigen-specific antibodies and through the phagocytic functions of naïve and memory B-cells. However, the B-cell response can become compromised by a variety of conditions that alter the overall inflammatory milieu, be that due to substantial, acute insults as seen in sepsis, or due to those that produce low-level, smoldering background inflammation such as diabetes, obesity, or advanced age. This B-cell dysfunction, mediated by the inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α), increases the susceptibility of late-stage sepsis patients to nosocomial infections and increases the incidence or severity of recurrent infections, such as SARS-CoV-2, in those with chronic conditions. We propose that modeling B-cell dynamics can aid the investigation of their responses to different levels and patterns of systemic inflammation.

Methods: The B-cell Immunity Agent-based Model (BCIABM) was developed by integrating knowledge regarding naïve B-cells, short-lived plasma cells, long-lived plasma cells, memory B-cells, and regulatory B-cells, along with their various differentiation pathways and cytokines/mediators. The BCIABM was calibrated to reflect physiologic behaviors in response to: 1) mild antigen stimuli expected to result in immune sensitization through the generation of effective immune memory, and 2) severe antigen challenges representing the acute substantial inflammation seen during sepsis, previously documented in studies on B-cell behavior in septic patients. Once calibrated, the BCIABM was used to simulate the B-cell response to repeat antigen stimuli during states of low, chronic background inflammation, implemented as low background levels of IL-6 and TNF-α often seen in patients with conditions such as diabetes, obesity, or advanced age. The levels of immune responsiveness were evaluated and validated by comparing to a Veteran's Administration (VA) patient cohort with COVID-19 infection known to have a higher incidence of such comorbidities.

Results: The BCIABM was successfully able to reproduce the expected appropriate development of immune memory to mild antigen exposure, as well as the immunoparalysis seen in septic patients. Simulation experiments then revealed significantly decreased B-cell responsiveness as levels of background chronic inflammation increased, reproducing the different COVID-19 infection data seen in a VA population.

Conclusion: The BCIABM proved useful in dynamically representing known mechanisms of B-cell function and reproduced immune memory responses across a range of different antigen exposures and inflammatory statuses. These results elucidate previous studies demonstrating a similar negative correlation between the B-cell response and background inflammation by positing an established and conserved mechanism that explains B-cell dysfunction across a wide range of phenotypic presentations.

Fig 1. NetLogo grid-space layout.

The black area represents the lymph node follicle, and the gray area represents the surrounding paracortex tissue. Each brown dot represents a follicular dendritic cell. Each blue and teal circle represents a helper T-cell. The afferent lymph flows into the follicle from the right side of the follicle and efferent lymph flows out on the left.

Fig 2. B-cell responses to mild antigen stimuli.

(A) Demonstrates the SLPC response. (B) Demonstrates the LLPC response. (C) Demonstrates the memory B-cell response. (D) Demonstrates the regulatory B-cell response. All four B-cell subtypes show a larger response upon second antigen exposure (day 60) compared to the first exposure (day 10). (B, C) The cells produced after the first and second exposure were color-coded black and red, respectively, in order to distinguish the magnitude of response for each exposure. This is necessary since the LLPCs and memory B-cells produced after the first exposure persist well into the second exposure. (A, D) The majority, if not all, of the cells produced after the first exposure die prior to the second exposure.

Fig 3. B-cell apoptosis, activation, and IL-10 levels during mild antigen stimuli.

(A) Shows the total number of B-cells that undergo apoptosis. There is no appreciable level of apoptosis upon first or second exposures. (B) Shows the average CD21 expression by naïve and memory B-cells. There is no change in CD21 expression upon first or second exposures. (C) Shows the total level of IL-10 secreted by regulatory B-cells. There is a slight increase in the IL-10 levels following second exposure compared to the first exposure, corresponding to the increased regulatory B-cell differentiation.

Fig 4. B-cell responses to severe antigen challenges seen in sepsis.

(A) Demonstrates the SLPC response. (B) Demonstrates the LLPC response. (C) Demonstrates the memory B-cell response. (D) Demonstrates the regulatory B-cell response. The SLPCs, LLPCs, and memory B-cells demonstrate a roughly 30-day period of low activity after the second exposure on day 60 corresponding to immunosuppresion. On the contrary, the anti-inflammatory regulatory B-cells demonstrate a large spike in activity. (B, C) The cells produced after the first and second exposure were color-coded black and red, respectively, in order to distinguish the magnitude of response for each exposure. This is required since the LLPCs and memory B-cells produced after the first exposure persist well into the second exposure. (A, D) The majority, if not all, of the cells produced after the first exposure die prior to the second exposure.

Fig 5. B-cell apoptosis, activation, and IL-10 during sepsis.

(A) Shows the total number of B-cells that undergo apoptosis. There is a significant increase in apoptosis after the septic antigen challenge on day 60. (B) Shows the average CD21 expression by naïve and memory B-cells. There is a significant decrease in CD21 expression, and therefore, level of activation, upon the septic antigen challenge. (C) Shows the total level of IL-10 secreted by regulatory B-cells. There is a large increase in the IL-10 levels following the septic exposure.

Fig 6. B-cell responses amidst increasing levels of background inflammation.

In all panels, the black line represents the B-cell response to the first exposure while the red line represents the response to the second exposure. (A) Shows the maximum SLPC responses in relation to background inflammation. (B)Shows the maximum LLPC responses. (C) Shows the maximum memory B-cell responses. (D) Shows the maximum regulatory B-cell responses.