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Immunoglobulins in Patients With Multiple Sclerosis

Learn about B cells and immunoglobulins, and hypogammaglobulinemia in Multiple Sclerosis (MS).

SECTIONS ON THIS PAGE

The Role of B Cells in MS
Immunoglobulins (Igs)
Hypogammaglobulinemia (HGG)
Prevalence
Monitoring and Management
Abbreviations

The Role of B Cells in MS

Development of Lymphocytes1

B Cells in MS

  • Recruitment and activation of autoimmune B cells may contribute to the development and progression of MS2
  • B cells may contribute to the development MS by producing proinflammatory cytokines and activating T cells in the central nervous system3

B-Cell Differentiation4

MS DMTs and B Cells

  • Some disease modifying therapies (DMTs) may reduce circulating levels of B cells5
  • Anti-CD20 treatments deplete CD20+ B cells but spare those without CD20 cell surface antigens (eg, stem cells and plasma cells)4-6

Footnote

  1. B cells enter the blood and migrate to secondary lymphoid tissues (eg, spleen and lymph nodes), where they encounter antigens and T-helper cells. There, B cells may undergo class switch recombination (to change the Ig class from IgM and IgD to IgG, IgA, or IgE) and somatic hypermutation.7,8

References

  1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Garland Science, 2017.
  2. Arneth BM. J Neuroinflammation. 2019;16(1):128.
  3. Rodríguez Murúa S, et al. Annu Rev Pathol. 2022;17:121-139.
  4. Forsthuber TG, et al. Ther Adv Neurol Disord. 2018;11;1756286418761697.
  5. Tallantyre EC, et al. Curr Opin Allergy Clin Immunol. 2018;18(6):481-488.
  6. Lehmann-Horn K, et al. J Neuroinflammation.
  7. Cyster JG, Allen CDC. Cell. 2019;177(3):524-540.2011;8:146.
  8. Akkaya M, et al. Nat Rev Immunol. 2020;20(4):229-238.

Immunoglobulins (Igs)

Igs play an important role in protective immunity, with functions including neutralization, opsonization, and complement activation.

Neutralization

Binding to pathogens or toxins to block their access to host cells1

Opsonization

Coating of pathogens or foreign particles to allow for engulfment by phagocytic cells1

Complement activation

Triggering a system of proteins, which may lead to phagocytosis or pathogen lysis1,2

Ig Effector Functions and Distributions in the Body3

Antibody class Function Distribution Serum Ig (%) Half-life
IgGa Main Ig in secondary immune response4
  • Blood and extravascular tissues4
  • Transported across the placenta4
 65%-75%4 ~23 days4
IgMa Early protection in primary immune response4
  • Blood, and less in lymph1
 ~10%4 5-10 days4
IgAa Protects mucosal surfaces4
  • Mucosal secretions1
  • Predominant Ig in breast milk4
 10%-15%4 4-7 days4
IgD Recognizes important respiratory pathogens3
  • Mucosal secretions5
 ~0.2%4 2-8 days4
IgE Associated with allergy and parasite reactivity4
  • Mucosal tissues3
 ~0.004%4 1-5 days4

Footnote

  1. Important antibodies for protective immunity.

References

  1. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. Garland Science, 2017.
  2. Garred P, et al. Pharmacol Rev. 2021;73(2):792-827.
  3. James LK. Clin Exp Immunol. 2022;210(3):230-239.
  4. Flajnik M, et al. Immunoglobulins: structure and function. In: Paul’s Fundamental Immunology. 8th ed. Wolters Kluwer Health, 2022:644-670.
  5. Chen K, Cerutti A. Curr Opin Immunol. 2011;23(3):345-352.

Hypogammaglobulinemia (HGG)

Overview of Hypogammaglobulinemia

Hypogammaglobulinemia is characterized by reduced immunoglobulin levels.1

Potential Clinical Consequences of Hypogammaglobulinemia:

  • Increased risk of infection2-5
  • Reduced response to vaccines1
Primary hypogammaglobulinemia
Due to primary immunodeficiencies and consisting of a variety of inherited disorders1,6
Secondary hypogammaglobulinemia
Due to disease processes or medications, such as immunosuppressive therapies1

The Lower Limit of Normal (LLN) for Immunoglobulins Varies Across Laboratories and Literature1

  IgG IgM IgA
Mayo Clinic7 767 mg/dL 37 mg/dL 61 mg/dL
Dati, et al8 700 mg/dL 40 mg/dL 70 mg/dL
Khan, et al9 620 mg/dL 28 mg/dL 86 mg/dL

Infections Associated With Immunoglobulin Deficiencies

IgG

Deficiency in IgG is most frequently implicated in increased risk of infection compared with IgM or IgA10

IgM

Deficiencies in IgM may potentially be associated with increased risk of infection11

IgA

IgA deficiency is often asymptomatic5

Low Immunoglobulin G Levels and Risk of Infection

Risk of infection may depend on the extent (particularly with IgG levels <400 mg/dL) and duration of hypogammaglobulinemia, as well as presence of other risk factors.2,10,12

There is no consensus in the stratification of low IgG levels for clinical studies. The AAAAI Working Group proposed the following categories1,a:

  • Hypogammaglobulinemia: serum IgG <700 mg/dL (in adults); further stratified:
    • 400-699 mg/dL (mild)
    • 200-399 mg/dL (moderate)
    • 0-199 mg/dL (severe)
  • Categories of duration: 3-6 months, 6-12 months, 12-24 months, >24 months

References

  1. Otani IM, et al. J Allergy Clin Immunol. 2022;149(5):1525-1560.
  2. Tallantyre EC, et al. Curr Opin Allergy Clin Immunol. 2018;18(6):481-488.
  3. Louis AG, et al. Clin Rev Allergy Immunol. 2014;46(2):104-111.
  4. Herrod HG. Allergy Proc. 1992;13(6):299-302.
  5. Swain S, et al. J Transl Autoimmun. 2019;2:100025.
  6. Bonilla FA, et al. J Allergy Clin Immunol. 2015;136(5):1186-1205.e1-78.
  7. Mayo Clinic Laboratories. https://www.mayocliniclabs.com/test-catalog/overview/ 8156#Clinical-and-Interpretive. Accessed June 6, 2023.
  8. Dati F, et al. Eur J Clin Chem Clin Biochem. 1996;34(6):517-520.
  9. Khan SM, et al. J Clin Immunol. 2021;41(8):1902-1914.
  10. Furst DE. Semin Arthritis Rheum. 2009;39(1):18-29.
  11. Kridin K, Ahmed AR. Autoimmun Rev. 2020;19(3):102466.
  12. Zoehner G, et al. Ther Adv Neurol Disord. 2019;12:1756286419878340.

Prevalence

Prevalence of Hypogammaglobulinemia in Multiple Sclerosis1

In a retrospective cross-sectional study, individuals with MS who were treated with DMTs had higher rates of IgG <LLN (<700 mg/dL) than controls.a

of patients with MS treated with DMTs
of DMT-naïve patients with MS
of controls without MS
  • IgM<LLN(<40 mg/dL): 12.2% of those with MS treated with DMTs and 0% of controls

Footnotes

  1. This study included 552 patients with MS.1

References

  1. Zoehner G, et al. Ther Adv Neurol Disord. 2019;12:1756286419878340

Monitoring and Management

Guidelines specifically for patients with MS and hypogammaglobulinemia are limited.1,2 Healthcare providers (HCPs) may refer to the prescribing information of the treatment being provided.

Screening and Monitoring
  • Screening for levels of Ig before initiating B-cell targeted therapy has been recommended2
  • Monitoring of Ig levels throughout treatment has been recommended for patients with MS on anti-CD20 therapy1
Management
  • For patients with hypogammaglobulinemia, HCPs may consult the AAAAI guidance on secondary hypogammaglobulinemia2
  • Clinical studies are needed to validate the recommendations provided for patients with neurological conditions, such as MS2

References

  1. The Consortium of Multiple Sclerosis Centers. https://cmscscholar.org/cmsc-practical-guidelines-for-the-selection-of-disease-modifying-therapies-in-ms. Accessed July 13, 2023.
  2. Otani IM, et al. J Allergy Clin Immunol. 2022;149(5):1525-1560.

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TOP

  • AAAAI
    American Academy of Allergy Asthma & Immunology

  • AE
    Adverse event

  • Ang2
    Angiopoietin-2

  • ARR
    Annualized Relapse Rate

  • ART
    Assisted Reproductive Technology

  • ASTCT
    American Society for Transplantation and Cellular Therapy

  • ATG
    Anti-thymocyte globulin

  • CAR
    Chimeric antigen receptor

  • CD3
    Cluster of differentiation 3

  • CD4
    Cluster of differentiation 4

  • CD8
    Cluster of differentiation 8

  • CD19
    Cluster of differentiation 19

  • CD20
    Cluster of differentiation 20

  • CD226
    Cluster of differentiation 226

  • CDC
    Centers for Disease Control and Prevention

  • CI
    Confidence Interval

  • COVID-19
    Coronavirus disease of 2019

  • CPAP
    Continuous positive airway pressure

  • CR
    Complete response

  • CRP
    C-reactive protein

  • CRS
    Cytokine release syndrome

  • CT
    Computed tomography

  • CTCAE
    Common Terminology Criteria for Adverse Events

  • DIC
    Disseminated intravascular coagulation

  • DLBCL
    Diffuse large B-cell lymphoma

  • DMT
    Disease-modifying therapy

  • DMT
    Disease-modifying treatment

  • DoCR
    Duration of complete response

  • DoR
    Duration of response

  • DBPCFC
    Double-blind, placebo-controlled food challenge

  • ECOG PS
    Eastern Cooperative Oncology Group performance status

  • ECTRIMS
    European Committee for Treatment and Research in Multiple Sclerosis

  • EDSS
    Expanded Disability Status Scale

  • EMA
    European Medicines Association

  • FAERS
    FDA Adverse Event Reporting System

  • FDA
    Food and Drug Administration

  • FDA
    US Food and Drug Administration

  • FL
    Follicular lymphoma

  • HCP
    Health Care Provider

  • HGBCL
    High-grade B-cell lymphoma

  • HLH
    Hemophagocytic lymphohistiocytosis

  • ICANS
    Immune effector cell-associated neurotoxicity syndrome

  • ICU
    Intensive care unit

  • Ig
    Immunoglobulin

  • IgE
    Immunoglobulin E

  • IgG1
    Immunoglobulin G1

  • INR
    International normalized ratio

  • IRC
    Independent Review Committee

  • IRR
    Infusion-related reaction

  • ITIM
    Immunoreceptor tyrosine-based inhibitory motif

  • LLN
    Lower limit of normal

  • LMP
    last menstrual cycle

  • LMP
    Last menstrual period

  • MAS
    Macrophage activation syndrome

  • MCA
    Major congenital anomalies

  • MHC
    Major histocompatibility complex

  • MS
    Multiple sclerosis

  • MSKCC
    Memorial Sloan Kettering Cancer Center

  • NK
    Natural killer

  • NO
    Nitric oxide

  • NOS
    Not otherwise specified

  • OB/Gyn
    Obstetrics and Gynecology

  • OCR
    OCREVUS (ocrelizumab)

  • OR
    Odds ratio

  • ORR
    Objective response rate

  • PD-1
    Programmed cell death protein 1

  • PD-L1
    Programmed death-ligand 1

  • PET
    Positron emission tomography

  • PFS
    Progression-free survival

  • PMBCL
    Primary mediastinal B-cell lymphoma

  • PML
    progressive multifocal leukoencephalopathy

  • PPMS
    Primary progressive multiple sclerosis

  • PTT
    Partial thromboplastin time

  • PVR
    Poliovirus receptor

  • RID
    Relative infant dose

  • RMS
    Relapsing multiple sclerosis

  • RRMS
    Relapsing-remitting multiple sclerosis

  • SAE
    Serious adverse event

  • T
    Trimester

  • TCR
    T-cell receptor

  • TIGIT
    T cell immunoreceptor with Ig and ITIM domains

  • UCSF
    University of California San Francisco

  • USPI
    United States Prescribing Information

  • URTI
    Upper respiratory tract infection

  • UTI
    Urinary tract infection

  • VWF
    von Wilebrand factor

  • NIH
    National Institutes of Health