What are age associated B cells (ABCs)?

Recent research reveals that a unique subset of immune cells, known as age-associated B cells (ABCs), accumulates in both elderly individuals and those with chronic inflammatory diseases. These cells represent a distinct B cell population with unique characteristics and functions, playing a complex and multifaceted role in immunity as we age.

Quick Summary

Age-associated B cells (ABCs) are a novel B cell subset that accumulates with age, in chronic infections, and in autoimmune diseases, contributing to both protective immune responses and pathogenic inflammation. They differ from conventional B cells in their activation signals, gene expression, and ability to differentiate into inflammatory antibody-producing cells.

Key Points

• ABCs accumulate with age: These unique B cell subsets increase in both number and frequency in the elderly, a hallmark of the aging immune system, and more so in females due to X-chromosome linked factors.

• Linked to autoimmunity and infection: ABCs expand prematurely in autoimmune diseases like lupus and rheumatoid arthritis, and also increase during chronic viral and parasitic infections, showing their dual capacity.

• Defined by unique markers: Characteristically, ABCs express high levels of CD11c and the transcription factor T-bet, while lacking markers like CD21 or CD27 (in human double-negative B cells) that define other B cell subsets.

• Promote inflammation: In autoimmune settings, ABCs function as potent antigen-presenting cells, secrete pro-inflammatory cytokines, and produce pathogenic autoantibodies that contribute to tissue damage.

• Activated by distinct signals: Unlike conventional B cells, ABC differentiation is driven by innate immune receptors (TLR7/9) and cytokines like IFN-γ and IL-21, rather than solely by antigen binding.

• A promising therapeutic target: Because of their role in autoimmune diseases, specifically targeting ABCs or their signaling pathways is being explored as a potential new therapeutic strategy to manage conditions like lupus and rheumatoid arthritis.

What are Age-Associated B Cells?

Age-associated B cells (ABCs) are a unique type of mature B lymphocyte identified by specific surface markers and a T-bet driven genetic program. They were first identified in 2011 and are found in higher numbers as people age, particularly in women, and in those with autoimmune diseases and long-term infections. Unlike standard B cells located in follicles, ABCs are often found in the spleen, bone marrow, and areas with inflammation. Their unique features and ability to participate in both beneficial and harmful immune responses make them a key area of immunology research.

Origins and Differentiation of ABCs

ABCs develop from existing B cells rather than directly from bone marrow. Differentiation is triggered by signals from innate and adaptive immunity, including TLR7/9 activation and cytokines like IFN-γ and IL-21. BCR signaling, especially with TLR activation, also plays a role. These signals lead to a genetic program resulting in distinct ABC features.

Distinctive Phenotype and Markers

Identifying ABCs involves specific markers. The table below highlights differences between ABCs and other B cell types.

Feature	Age-Associated B Cells (ABCs)	Follicular B Cells (FO)	Conventional Memory B Cells
Key Surface Markers	High CD11c, T-bet+	CD21+, CD23+, CD11c-	CD27+, CD21+
CD21 Expression	Low or absent	High	High
IgD/CD27 Status (Human)	IgD−CD27− (Double-Negative)	IgD+	CD27+IgD−
Activation Signal	Innate TLRs + Cytokines	BCR + T cell help	Re-stimulation by Ag
Survival Factor	BAFF-independent	BAFF-dependent	Generally BAFF-independent
Primary Function	Antigen presentation, inflammation, autoantibody production	Antibody production in germinal centers	Rapid antibody recall response

Physiological and Pathological Functions

ABCs play a dual role in immunity and disease.

Role in Healthy Aging and Infections

ABCs contribute positively in healthy aging and infections, producing antibodies and cytokines against viruses and presenting antigens to T cells. Their increase with age is linked to low-level inflammation.

Role in Autoimmune Diseases

ABCs' harmful effects are seen in autoimmune disorders, driving inflammation and autoantibody production. They contribute via autoantibody production, enhanced antigen presentation to T cells, and secretion of inflammatory cytokines. ABCs accumulate in inflamed tissues in conditions like SLE and RA.

Therapeutic Potential Targeting ABCs

ABCs are a potential therapeutic target in autoimmune conditions. Current broad B cell therapies exist, but specific ABC targeting is being explored to reduce side effects.

Strategies include targeting signaling pathways like TLR7/9, blocking B-cell survival factors like BAFF, and inhibiting the T-bet protein. Research is ongoing to validate these approaches in humans. For more information on B cell mediated diseases, consult resources like the {Link: British Society for Immunology https://www.immunology.org/public-information/bitesized-immunology/immune-dysfunction/b-cell-mediated-disease}.

Conclusion

Age-associated B cells are a complex subset involved in aging, infection, and autoimmunity. Their prevalence with age and inflammation highlights their importance in understanding immune changes and disease development. Research into ABC development and function may lead to more precise treatments for inflammatory and autoimmune conditions.

Frequently Asked Questions

What is the primary role of age-associated B cells (ABCs) in the immune system?

ABCs have a complex, dual role. In a healthy context, they can contribute to protective antiviral responses and long-term memory. However, in autoimmune diseases, they become pathogenic by promoting inflammation, acting as efficient antigen-presenting cells, and producing autoantibodies.

How do ABCs differ from other B cell types?

ABCs differ in their activation requirements, unique surface markers, and transcriptional profile. For instance, they rely heavily on innate immune signals (TLR7/9) and specific cytokines (IFN-γ, IL-21) for activation, unlike conventional B cells that primarily depend on B cell receptor (BCR) stimulation. They also express high levels of T-bet and CD11c and are often defined by a low or absent CD21 marker.

Are ABCs always harmful, or can they be beneficial?

ABCs are not always harmful. While they are associated with pathogenic outcomes in autoimmune diseases, they also play a protective role in response to chronic viral infections by producing antiviral antibodies and helping clear the pathogen. Their effect depends on the specific inflammatory context in which they are activated.

Which diseases are linked to the expansion of ABCs?

The abnormal expansion of ABCs is linked to several autoimmune and inflammatory diseases. These include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome, and multiple sclerosis (MS). They also accumulate during chronic infections like HIV and malaria.

Why do ABCs increase with age?

The accumulation of ABCs with age is part of a phenomenon called immunosenescence. The chronic inflammatory environment associated with aging, referred to as 'inflammaging,' provides the necessary signaling cues for ABC differentiation and expansion. This process appears to be particularly pronounced in females.

How do researchers identify ABCs?

Researchers identify ABCs using flow cytometry to detect specific combinations of cell surface markers. Common markers include high expression of CD11c and the transcription factor T-bet, along with low or absent expression of CD21. In humans, they are often defined as a double-negative (IgD−CD27−) B cell subset.

Can ABCs be targeted for therapeutic purposes?

Yes, targeting ABCs is a promising area of research. Therapies that block specific activation pathways, such as TLR signaling, or deplete B cell populations, like Belimumab, have shown potential. However, researchers are focused on developing more specific therapies to target only pathogenic ABCs without affecting beneficial immune cells.