Official reprint from UpToDate®
www.uptodate.com ©2015 UpToDate®

The humoral immune response

Francisco A Bonilla, MD, PhD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Anna M Feldweg, MD


The term "humoral" refers to the liquid, noncellular components of the blood and other tissues, such as plasma and lymphatic fluid. The humoral immune response denotes immunologic responses that are mediated by antibodies. However, both B and T lymphocytes as well as dendritic cells and other antigen-presenting cells are necessary for the formation of antigen-specific antibody.

Natural antibodies — "Natural antibodies" are so-called because they are produced naturally, without any antigen exposure. Vertebrate animals, even in germ-free environments, produce natural antibodies. For human infants, these antibodies, along with maternal immunoglobulin G (IgG) that is transported across the placenta into the fetus in the third trimester of gestation, are important for protection of the newborn. Immediately after birth, neonates leave a sterile environment and are bombarded by microbes and other antigens. Therefore, antigen-stimulated antibody production is rapidly superimposed on natural antibodies. However, that process takes time (months) and in the interim, natural antibody and maternal antibody are important.

Natural antibodies are often polyspecific, meaning that they react with multiple endogenous and/or exogenous antigens bearing no readily identifiable structural similarity (eg, histones, polynucleotides, other immunoglobulins). Some recognize "oxidation-specific" epitopes, which are epitopes generated during the oxidative processes involved in metabolism, aging, and inflammation. These epitopes are ubiquitous on both microbes and aging and apoptotic host cells and represent a class of pathogen- or damage-associated molecular pattern (PAMP or DAMP) recognized by receptors of the innate immune system. Thus, natural antibodies appear to function as a type of pattern recognition receptor (PRR) for these molecular structures. Natural antibodies are primarily of the immunoglobulin M (IgM) isotype. They are produced by a distinct subset of B cells known as B-1 cells, which produce antibody without any requirement of prior antigenic stimulation [1].

Natural antibodies appear to have at least two important functions. The first is to provide early protection against infections with a rapid immune response against pathogens, before more specific antibodies can be produced. The second role is assisting in homeostasis by binding to aging and apoptotic cells and cellular debris, which if not cleared, could create a proinflammatory and immunogenic environment. Natural antibodies are discussed further elsewhere. (See "Function and clinical applications of immunoglobulins", section on 'Natural antibodies'.)

Humoral immunity includes the primary and secondary immune responses to antigen. During the primary immune response, an antigen is encountered by the host for the first time. Virgin B cells need to be activated and proliferate before an effective antibody response can be generated. This primary antibody response may be too slow to protect against many pathogens, therefore polyspecific natural antibodies with low affinity and the innate immune system may be utilized to limit microbial replication at the onset of infection. By comparison, the secondary antibody response, which results from the activation of a memory B cell, is faster and more effective in halting the progress of infection due to increased antibody-binding affinities.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Oct 2015. | This topic last updated: Mar 23, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2015 UpToDate, Inc.
  1. Rothstein TL, Griffin DO, Holodick NE, et al. Human B-1 cells take the stage. Ann N Y Acad Sci 2013; 1285:97.
  2. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715.
  3. Jolliff CR, Cost KM, Stivrins PC, et al. Reference intervals for serum IgG, IgA, IgM, C3, and C4 as determined by rate nephelometry. Clin Chem 1982; 28:126.
  4. McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol 2005; 23:487.
  5. Baumgarth N. A two-phase model of B-cell activation. Immunol Rev 2000; 176:171.
  6. Clark EA, Lane PJ. Regulation of human B-cell activation and adhesion. Annu Rev Immunol 1991; 9:97.
  7. Cruchley AT, Williams DM, Niedobitek G, Young LS. Epstein-Barr virus: biology and disease. Oral Dis 1997; 3 Suppl 1:S156.
  8. Thornton BP, Vĕtvicka V, Ross GD. Natural antibody and complement-mediated antigen processing and presentation by B lymphocytes. J Immunol 1994; 152:1727.
  9. Tedder TF, Zhou LJ, Engel P. The CD19/CD21 signal transduction complex of B lymphocytes. Immunol Today 1994; 15:437.
  10. Kosco-Vilbois MH, Gray D, Scheidegger D, Julius M. Follicular dendritic cells help resting B cells to become effective antigen-presenting cells: induction of B7/BB1 and upregulation of major histocompatibility complex class II molecules. J Exp Med 1993; 178:2055.
  11. Coutinho A, Gronowicz E, Moller G. Activation of lymphocytes by antigen and mitogen. In: Regulation of growth and differentiated function in eukaryote cells, Talwar GP (Ed), Raven Press, New York 1975. p.213.
  12. Vos Q, Lees A, Wu ZQ, et al. B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol Rev 2000; 176:154.
  13. Richards S, Watanabe C, Santos L, et al. Regulation of B-cell entry into the cell cycle. Immunol Rev 2008; 224:183.
  14. Küppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol 2003; 3:801.
  15. Castigli E, Wilson SA, Scott S, et al. TACI and BAFF-R mediate isotype switching in B cells. J Exp Med 2005; 201:35.
  16. von Bülow GU, van Deursen JM, Bram RJ. Regulation of the T-independent humoral response by TACI. Immunity 2001; 14:573.
  17. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005; 37:829.
  18. Salzer U, Chapel HM, Webster AD, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005; 37:820.
  19. Peng SL. Signaling in B cells via Toll-like receptors. Curr Opin Immunol 2005; 17:230.
  20. Huggins J, Pellegrin T, Felgar RE, et al. CpG DNA activation and plasma-cell differentiation of CD27- naive human B cells. Blood 2007; 109:1611.
  21. Mills DM, Cambier JC. B lymphocyte activation during cognate interactions with CD4+ T lymphocytes: molecular dynamics and immunologic consequences. Semin Immunol 2003; 15:325.
  22. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 2004; 22:307.
  23. Grammer AC, Slota R, Fischer R, et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin Invest 2003; 112:1506.
  24. Ferrari S, Plebani A. Cross-talk between CD40 and CD40L: lessons from primary immune deficiencies. Curr Opin Allergy Clin Immunol 2002; 2:489.
  25. Fulcher DA, Basten A. B-cell activation versus tolerance--the central role of immunoglobulin receptor engagement and T-cell help. Int Rev Immunol 1997; 15:33.
  26. Hobeika E, Nielsen PJ, Medgyesi D. Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med (Berl) 2015; 93:143.
  27. Morgan EL, Hobbs MV, Thoman MT, Weigle WO. Lymphocyte activation by the Fc region of immunoglobulins. Immunol Invest 1986; 15:625.
  28. Pincus CS, Nussenzweig V. Passive antibody may simultaneously suppress and stimulate antibody formation against different portions of a protein molecule. Nature 1969; 222:594.
  29. Chacko GW, Tridandapani S, Damen JE, et al. Negative signaling in B lymphocytes induces tyrosine phosphorylation of the 145-kDa inositol polyphosphate 5-phosphatase, SHIP. J Immunol 1996; 157:2234.
  30. Kurosaki T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2002; 2:354.
  31. Rajewsky K. Clonal selection and learning in the antibody system. Nature 1996; 381:751.
  32. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117.
  33. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular dynamics. Immunity 2007; 27:190.
  34. McKendall RR, Pettit M, Woo W. The immunoglobulin response to individual HSV-1 viral polypeptides: kinetics of the response during primary and secondary experimental infection with herpes simplex virus. J Med Microbiol 1988; 25:59.
  35. Gysin J, Fandeur T, Pereira da Silva L. Kinetics of the humoral immune response to blood-induced falciparum malaria in the squirrel monkey Saimiri sciureus. Ann Immunol (Paris) 1982; 133D:95.
  36. Welliver RC, Kaul TN, Putnam TI, et al. The antibody response to primary and secondary infection with respiratory syncytial virus: kinetics of class-specific responses. J Pediatr 1980; 96:808.
  37. Tangye SG, Avery DT, Deenick EK, Hodgkin PD. Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses. J Immunol 2003; 170:686.
  38. Foote J, Milstein C. Kinetic maturation of an immune response. Nature 1991; 352:530.
  39. Berek C, Milstein C. The dynamic nature of the antibody repertoire. Immunol Rev 1988; 105:5.
  40. Allen D, Cumano A, Dildrop R, et al. Timing, genetic requirements and functional consequences of somatic hypermutation during B-cell development. Immunol Rev 1987; 96:5.
  41. Gatto D, Martin SW, Bessa J, et al. Regulation of memory antibody levels: the role of persisting antigen versus plasma cell life span. J Immunol 2007; 178:67.
  42. Gray D, Bergthorsdottir S, van Essen D, et al. Observations on memory B-cell development. Semin Immunol 1997; 9:249.
  43. Lane P. Development of B-cell memory and effector function. Curr Opin Immunol 1996; 8:331.
  44. Gray D, Skarvall H. B-cell memory is short-lived in the absence of antigen. Nature 1988; 336:70.
  45. Liu YJ, Barthélémy C, de Bouteiller O, et al. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity 1995; 2:239.
  46. Liu YJ, Zhang J, Lane PJ, et al. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol 1991; 21:2951.