What are plasma cells?

Plasma Cells: Specialized Antibody-Producing Immune Cells

Plasma cells are terminally differentiated B lymphocytes that specialize in antibody production and secretion, serving as the primary effector cells of humoral immunity. 1 These highly specialized cells represent the final stage of B cell development and are essential for maintaining immune protection against pathogens.

Characteristics and Morphology

Plasma cells have distinct morphological features that help identify them:

• Round or oval shape with characteristic basophilic cytoplasm
• Eccentric nucleus containing coarse heterochromatin (clock-face appearance)
• Lack of surface immunoglobulin expression when fully mature
• Identifiable by co-expression of CD138 and CD38 markers 2
• Typically found in bone marrow, lymphoid tissues, and sites of inflammation

Development and Differentiation

The development of plasma cells follows a specific pathway:

1. Activation: Mature B cells are activated by antigen exposure
2. Germinal center formation: Activated B cells undergo proliferation and selection
3. Plasmablast stage: Initial antibody-secreting cells that can still divide
4. Terminal differentiation: Formation of either:
   • Short-lived plasma cells (days to weeks)
   • Long-lived plasma cells (months to years)

Immunophenotype

Plasma cells display a characteristic immunophenotype that distinguishes them from other immune cells:

• Core markers: CD38 and CD138 (syndecan-1) are the primary identifiers 3
• Variable expression: CD20, CD56, CD117, and HLA-DR expression varies between normal plasma cells and malignant forms
• Diagnostic importance: Flow cytometry using these markers helps identify abnormal plasma cell populations in conditions like plasma cell leukemia and multiple myeloma

Functions

Primary Function: Antibody Production

Plasma cells are the body's antibody factories:

• Constitutively secrete large amounts of antibodies
• Can produce up to 10,000 antibody molecules per second
• Maintain humoral immunity through continuous antibody secretion 4
• Quality and quantity of antibodies are key determinants of vaccine efficacy

Beyond Antibody Secretion

Recent research has revealed additional functions of plasma cells:

• Cytokine production: Can secrete various cytokines affecting immune responses
• Immune regulation: May act as antigen-presenting cells
• Bone homeostasis: Influence bone remodeling processes
• Hematopoiesis regulation: Can affect blood cell production 5

Plasma Cell Subpopulations

Plasma cells exhibit considerable heterogeneity:

1. Short-lived plasma cells:

   • Survive for days to weeks
   • Respond to immunosuppressive drugs and B cell-targeting therapies
   • Responsible for immediate antibody responses
   • Often found in extrafollicular regions of lymphoid tissues 1

2. Long-lived plasma cells:

   • Survive for months to years in specialized niches
   • Independent of B cell help or antigen contact
   • Resistant to conventional immunosuppressants
   • Primarily reside in bone marrow microenvironmental niches 6

Metabolic Requirements

Plasma cell longevity and function depend heavily on metabolism:

• High glucose uptake and catabolism support longevity
• Nutrient availability affects respiratory capacity and antibody secretion
• Metabolic pathways are primarily regulated non-transcriptionally
• Endoplasmic reticulum stress influences plasma cell survival 4

Clinical Significance

Diagnostic Criteria in Plasma Cell Disorders

In plasma cell leukemia (PCL), diagnostic criteria include:

• ≥20% circulating plasma cells in peripheral blood and/or
• Absolute count >2×10⁹/L plasma cells 3, 7

Even lower values (≥5% or ≥0.5×10⁹/L) may represent early PCL requiring intervention 7.

Role in Disease

Plasma cells contribute to various pathological conditions:

1. Autoimmune disorders: Production of pathogenic autoantibodies
2. Allergies: Secretion of IgE antibodies
3. Transplant rejection: Production of donor-specific antibodies
4. Plasma cell dyscrasias: Multiple myeloma, plasma cell leukemia, and other malignancies 1, 6

Therapeutic Implications

Targeting pathogenic plasma cells presents unique challenges:

• Short-lived plasma cells can be depleted by steroids and cytostatic drugs
• Long-lived plasma cells are resistant to conventional therapies
• Proteasome inhibitors (like bortezomib) can target long-lived plasma cells
• Immunoablative therapy with antithymocyte globulin may be effective in severe cases
• Antigen-specific elimination approaches are being developed to preserve protective plasma cells 1, 6

Common Pitfalls in Plasma Cell Evaluation

• Inadequate sampling for accurate plasma cell percentage assessment
• Misidentification without proper flow cytometry confirmation
• Overlooking non-malignant causes of plasma cell presence in peripheral blood
• Delay in diagnosis when circulating plasma cells are detected 7

Plasma cells represent a fascinating cell type whose importance extends far beyond antibody production. Understanding their biology is crucial for developing effective therapies for antibody-mediated diseases and plasma cell malignancies.