Pure B-Cell Disorders - Causes, Symptoms, Diagnosis, and Treatment

What Is a B-Cell?

B-cells are a subdivision of white blood cells (leukocytes) and are termed B-lymphocytes. They originate from the hematopoietic stem cells present in the bone marrow and mature in the peripheral lymphoid tissues. ‘B’ in B-cells stands for bursa of Fabricius (lymphoid tissue present in birds) which is an analog to human lymphoid tissue.

B-cells exhibit humoral immunity and produce various types of antibodies or immunoglobulins(Ig). These antibodies express adaptive immunity where they recognize and attack the antigens present in the infectious agents. They also remember the antigen and the same class of antibodies are produced in reinfection.

What Are Pure B-Cell Disorders?

Defective or altered production and maturation of B-cells leads to B-cell disorders. These disorders are broadly classified into,

• Primary Immunodeficiencies - Decreased antibody production or impaired development of B-cell.

• B-Cell Malignancies - Uncontrolled and excessive proliferation of B-cells in the bone marrow (lymphomas and leukemias).

Pure B-Cell Disorders - refers to primary immunodeficiencies that occur due to impairment in antibody production. Pure B-cell disorders lead to reduced levels and decreased function of antibodies (immunoglobulins) in the affected individuals. Though lymphomas and leukemias originate from B-cells, they are classified as malignancies and not as pure B-cell disorders due to their difference in pathogenesis and vivid clinical manifestations.

What Are the Types of Pure B-Cell Disorders?

Pure B-cell disorders are categorized based on the following criteria:

• Type 1 - Massive reduction in all immunoglobulin isotypes (IgG, IgM, IgA, IgE, and IgD) with excessive decrease or complete absence of B cells (agammaglobulinemia).

• Type 2 - Marked reduction in at least two immunoglobulin isotypes (IgG and IgA) with a normal or decreased number of B cells (CVID phenotype).

• Type 3 - Excessive reduction in IgG and IgA with normal or elevated IgM and normal numbers of B cells (Hyper IgM syndrome).

• Type 4 - Light chain, isotype, and functional deficiencies with normal numbers of B cells.

Type 1 - Massive Reduction in All Immunoglobulin Isotypes / Excessive Decrease or Complete Absence of B Cells (Agammaglobulinemia).

• X-linked agammaglobulinemia (XLA) or BTK (Bruton's tyrosine kinase) deficiency.

• μ heavy chain deficiency.

• λ 5 deficiency.

• Igα deficiency.

• Igβ deficiency.

• BLNK deficiency.

• PIK3R1 deficiency.

• E47 transcription factor deficiency.

Type 2 - Marked Reduction in at Least Two Immunoglobulin Isotypes/Normal or Decreased Number of B Cells - Common Variable Immune Deficiency (CVID) Phenotype.

• CVID of unknown gene defect.

• TACI deficiency.

• BAFF receptor deficiency.

• TWEAK deficiency.

• CD (cluster of differentiation) 19 deficiency.

• CD81 deficiency.

• CD20 deficiency.

• CD21 deficiency.

• LRBA deficiency.

• CTLA4 deficiency.

• PIK3CD mutation (GOF).

• NFκBI deficiency.

• NFκB2 deficiency.

Type 3 - Excessive Reduction in Igg and Iga/Normal or Elevated IgM and Normal Numbers of B Cells ( Hyper IgM Syndrome).

• CD40L deficiency.

• CD40 deficiency.

• AID deficiency.

• UNG deficiency.

Type 4 - Light Chain, Isotype, and Functional Deficiencies With Normal Numbers of B Cells.

• Ig heavy chain mutations and deletions.

• Kappa chain deficiency.

• Isolated IgG subclass deficiency.

• IgG-subclass deficiency with IgA deficiency.

• Selective IgA deficiency.

• Specific antibody deficiency with normal Ig levels and normal B cells.

• Transient hypogammaglobulinemia of infancy.

• Selective IgM deficiency.

What Are the Causes of Pure B-Cell Disorders?

Pure B-cell disorders occur due to a spectrum of heterogeneous causes. The various factors that cause pure B-cell disorders are as follows:

• Intrinsic molecular defects within B-cells.

• Genetic inheritance (x-linked, autosomal dominant, autosomal recessive).

• Congenital defects.

• Blockage in the interaction between B-cells and T-cells (T-lymphocytes).

• Loss or absence of responses from specific bone marrow germinal centers (sites of antibody production).

• Defective immune regulation.

Secondary Causes - Underlying pure B-cell disorders that remain asymptomatic sometimes get triggered due to stimulating factors such as:

• Post-transfusion reactions.

• Post-vaccine responses.

• Medications such as anticonvulsants.

• Disease-modifying anti-rheumatic drugs.

• Nonsteroidal anti-inflammatory drugs.

What Are the Clinical Manifestations of Pure B-Cell Disorders?

In general. individuals with B-cell disorders typically present with variable clinical expressions and recurrent infections. The severity of the clinical symptoms and complications vary according to the type of defects in B-cell development and the degree of its impaired function.

• Severe bacterial infections.

• Recurrent bacterial infections.

• Recurrent sinopulmonary and mucosal infections.

• Enteropathy.

• Autoimmune granulomatous and lymphoproliferative complications (Bronchiectasis).

• Pneumonia.

• Warts.

• Thrombocytopenia.

• Neutropenia.

• Glomerulonephritis.

• Autoimmune cytopenias.

• Endocrinopathy.

• Chronic obstructive pulmonary disease (COPD).

• Epstein-Barr virus infection and complications.

• Alopecia.

• Autoimmune thyroiditis.

• opportunistic infections.

• Enlarged lymph nodes and germinal centers.

• Poor antibody response to specific antigens.

• Recurrent viral infections.

• Reduced ability to produce antibodies to specific antigens (especially vaccines).

• Pneumococcal bacterial infections.

• Increased susceptibility to malignancy(particularly non-Hodgkin's lymphoma).

• Infections in the central nervous system (Cryptococcus and Toxoplasma).

• Cellulitis.

• Lymphadenitis.

• Gastrointestinal infections.

• Hepatitis.

• Inflammatory bowel disease.

• Arthritis.

• Allergic rhinitis.

How Are Pure B-Cell Disorders Diagnosed?

Diagnosing a pure B-cell disorder first starts with a detailed clinical history and then followed by confirmatory laboratory investigations. An elaborate family history, history of past infections, age of onset of clinical symptoms, duration and frequency of treatment undergone, and previous test reports. The diagnostic investigations for pure B-cell disorders are as follows:

• Complete blood count.

• Full evaluation of lymphocyte panels (T-cell, B-cell, and NK-cell subsets).

• Quantitative plasma immunoglobulin levels (IgM, IgG, IgA, IgD, and IgE).

• Evaluation of targeted antibody responses to antigens (both protein and polysaccharide).

• Hypogammaglobulinemia is seen in type-1 B-cell disorders (IgG < 5 g/L).

• Marked reduction of IgA (< 0.8 g/L) and IgM (< 0.4 g/L) in type-2 disorders.

• Lymph node biopsy shows abnormal lymphoid tissues with decreased activity.

• Polymerase chain reaction (PCR) helps to identify specific immunoglobulin which is defective.

• Imaging of the chest cavity shows mediastinal lymphadenopathy and enlarged lymph nodes.

• Immunophenotyping of B-cells to categorize the type of B-cell disorder.

• Gene sequencing identifies known and unknown gene defects and also detects panels of primary antibody deficiencies.

• Molecular diagnosis helps in deciding treatment optimization and as an accurate guide to genetic counseling.

What Are Therapeutic Interventions for Pure B-Cell Disorders?

The primary rule for the treatment of all pure B-cell disorders (regardless of the molecular defect) is immunoglobulin replacement therapy. Adjuvant therapies like bone marrow transplantation are most effective in treating B-cell disorders. The therapeutic interventions for pure B-cell disorders are as follows:

• Intravenous immunoglobulin (IVIG) is given at regular periodic intervals depending on the severity of the clinical conditions.

• Prophylactic administration of immunoglobulin preparations that are prepared by cold alcohol fractionation from pooled human plasma.

• Rapid subcutaneous immunoglobulin infusion is found to be an effective method of administration.

• Hematopoietic stem cell therapy (HSCT) has been proven to improve antibody production in B-cell immunodeficiencies.

• Allogeneic stem cell transplantation and bone marrow transplantation are used in the treatment of CVID patients.

• Gene therapy is employed to correct immunodeficiencies at the genetic level.

Conclusion

Pure B-cell disorders represent a broad class of immunodeficiencies characterized by defective antibody functioning. The affected individuals show diverse clinical diseases and are prone to infections. Advanced diagnostics to detect genetic defects help in understanding the treatment outcome. Prophylactic treatments and management of clinical symptoms help to prevent severe complications and lower morbidity incidence.