Hypergammaglobulinemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]
Overview
Hypergammaglobulinemia is an immunoproliferative disorder with elevated levels of gamma globulin (immunoglobulins or antibodies).[1][2]
Pathophysiology
- Hypergammaglobulinemia is an immunoproliferative disorder which arises from B cells, which are a type of white cells that are normally involved in the development of humoral immunity by secreting antibodies.[3]
- The majority of the hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM) because this is the default immunoglobulin type prior to class switching.[1]
- Hypergammaglobulinemias may also be caused by a deficiency in the other major types of immunoglobulins.[1][4]
- The term "hypergammaglobulinemia" refers to the position of the excess of proteins after serum protein electrophoresis (found in the gammaglobulin region).[1]
Normal Mechanism of Immunoglobulin Class Switching
- Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulins (antibodies) from one type to another, such as from the isotype IgM to the isotype IgG.
- Naïve mature B cells produce both IgM and IgD, which are the first two heavy chain segments in the immunoglobulin locus.
- After activation by the antigen, the B cells proliferate. If these activated B cells encounter specific signaling molecules via their CD40 and cytokine receptors (both modulated by T helper cells), they undergo antibody class switching to produce IgG, IgA or IgE antibodies.
- During class switching, the constant region of the immunoglobulin heavy chain changes but the variable regions, and therefore antigenic specificity, stay the same. This allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes (e.g. IgG1 and IgG2).[5]
- Class switching occurs by a mechanism called class switch recombination (CSR) binding.[6]
- During CSR, portions of the antibody heavy chain locus are removed from the chromosome, and the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype.
- Double-stranded breaks are generated in DNA at conserved nucleotide motifs, called switch (S) regions, which are upstream from gene segments that encode the constant regions of antibody heavy chains.
- DNA is nicked and broken at two selected S-regions by the activity of a series of enzymes, including Activation-Induced (Cytidine) Deaminase (AID), uracil DNA glycosylase and apyrimidic/apurinic (AP)-endonucleases.[7][5]= 11 | pages= 1101-3 | pmid=15496946 | doi=10.1038/ni1104-1101 | pmc=PMC4625794 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15496946 }} </ref>
- The intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant region exons and allowing substitution of a γ, α or ε constant region gene segment.
- The free ends of the DNA are rejoined by a process called non-homologous end joining (NHEJ) to link the variable domain exon to the desired downstream constant domain exon of the antibody heavy chain.[8]
- In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins.[9]
-
![Mechanism of class-switch recombination that allows isotype switching in activated B cells[10]](/images/b/b3/Class_switch_recombination.png)
Mechanism of class-switch recombination that allows isotype switching in activated B cells[10]
![Mechanism of class-switch recombination that allows isotype switching in activated B cells[10]](/index.php/File:Class_switch_recombination.png)
Type 1 hypergammaglobulinemia
- Type 1 hypergammaglobulinemia is transmitted in x-linked recessive pattern and is the most common type of hypergammaglobulinemia.
- A mutation in the tumor necrosis factor super family member 5 (TNFSF5) gene which normally codes for CD40 ligand is involved in the pathogenesis of type 1 hypergammaglobulinemia.[1]
- In addition to isotype class switching, CD40 ligand is also necessary for other functions of T-lymphocytes and therefore, patients with X-linked hyper IgM syndrome have defective cellular immunity and are at an increased risk for opportunistic infections.[11]
Type 2 hypergammaglobulinemia
The function of these genes is limited to antibody switching, so the other T-lymphocyte functions of CD40 ligand are not affected, and these patients are less likely to have opportunistic infections or cancer.
Microscopic Pathology
- On lymph node biopsy, x-linked hypergammaglobulinemia is characterized by the absence of germinal centers.[6]
- Ineffective CD40L-CD40 interaction in the extrafollicular areas results in poor recruitment of germinal center precursors
- On lymph node biopsy, approximately two-thirds of patients with autosomal recessive hyper-IgM are characterized by lymphoid hyperplasia which clinically presents as prominent cervical lymphadenopathy and tonsillar hypertrophy.[6]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.
- ↑ Globulin. Wikipedia. https://en.wikipedia.org/wiki/Globulin. Wikipedia. Accessed on February 24, 2016.
- ↑ B cell. Wikipedia. https://en.wikipedia.org/wiki/B_cell Accessed on February 24, 2016.
- ↑ Immunoproliferative disorder. Wikipedia. Accessed on February 24, 2016.
- ↑ 5.0 5.1 Durandy A (2003). "Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation". Eur J Immunol. 33 (8): 2069–73. doi:10.1002/eji.200324133. PMID 12884279.
- ↑ 6.0 6.1 6.2 Fried AJ, Bonilla FA (2009). "Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections". Clin Microbiol Rev. 22 (3): 396–414. doi:10.1128/CMR.00001-09. PMC 2708392. PMID 19597006.
- ↑ Casali P, Zan H (2004). "Class switching and Myc translocation: how does DNA break?". Nat Immunol. 5 (11): 1101–3. doi:10.1038/ni1104-1101. PMC 4625794. PMID 15496946.
- ↑ Lieber MR, Yu K, Raghavan SC (2006). "Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations". DNA Repair (Amst). 5 (9–10): 1234–45. doi:10.1016/j.dnarep.2006.05.013. PMID 16793349.
- ↑ Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M; et al. (2007). "IgH class switching and translocations use a robust non-classical end-joining pathway". Nature. 449 (7161): 478–82. doi:10.1038/nature06020. PMID 17713479.
- ↑ Immunoglobulin class switching. Wikipedia. https://en.wikipedia.org/wiki/Immunoglobulin_class_switching. AccessedonFebruary 29, 2016.
- ↑ Hyper IgM Syndromes. Immune Deficiency Foundation. http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/hyper-igm-syndromes/ Accessed on March 1, 2016.