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| ==Overview== | | ==Overview== |
| | Hypergammaglobulinemia is a primary immunodeficiency disease with an elevated concentration of gamma globulins (immunoglobulins or antibodies).<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref><ref>Globulin. Wikipedia. https://en.wikipedia.org/wiki/Globulin. Wikipedia. Accessed on February 24, 2016.</ref> The term "hypergammaglobulinemia" refers to the position of the excess of proteins after serum protein electrophoresis (found in the gammaglobulin region).<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref> The majority of hypergammaglobulinemias are caused by an excess of immunoglobulin M (IgM) because this is the default immunoglobulin type prior to class switching.<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref> Hypergammaglobulinemias may also be caused by a deficiency in the other major types of immunoglobulins.<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref><ref>Immunoproliferative disorder. Wikipedia. Accessed on February 24, 2016.</ref> |
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| ==Classification== | | ==Classification== |
| *Hyper IgM associated hypergammaglobulinemias may be classified into the following five types:<ref>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016</ref><ref name=OMIM>Immunodeficiency with hyper-IgM, Type 1; HIGM1. http://www.omim.org/entry/308230. Accessed on February 24, 2016</ref>
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| ! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Type}}
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| ! style="background: #4479BA; width: 370px;" | {{fontcolor|#FFF|Gene involved}}
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| ! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Mode of inheritance}}
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align=center |
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| Type 1
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| | style="padding: 5px 5px; background: #F5F5F5;" |
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| *Tumor Necrosis Factor Super Family member 5 (''TNFSF5'') gene
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| X-linked recessive
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| Type 2
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| | style="padding: 5px 5px; background: #F5F5F5;" |
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| *Activation-Induced Cytidine Deaminase (''AICDA'') gene
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align=center |
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| Autosomal recessive
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| Type 3
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| *''CD40'' gene
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| Autosomal recessive
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| Type 4
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| *Not yet known
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| Type 5
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| *Gene encoding Uracil-DNA glycosylase
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| | style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" align=center |
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| Autosomal recessive
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| |}
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| ==Pathophysiology==
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| *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.<ref>B cell. Wikipedia. https://en.wikipedia.org/wiki/B_cell Accessed on February 24, 2016.</ref>
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| *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.<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref>
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| *Hypergammaglobulinemias may also be caused by a deficiency in the other major types of immunoglobulins.<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref><ref>Immunoproliferative disorder. Wikipedia. Accessed on February 24, 2016.</ref>
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| *The term "hypergammaglobulinemia" refers to the position of the excess of proteins after serum protein electrophoresis (found in the gammaglobulin region).<ref name=kb>Hypergammaglobulinemia. Wikipedia. https://en.wikipedia.org/wiki/Hypergammaglobulinemia Accessed on February 24, 2016.</ref>
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| ===Normal Mechanism of Immunoglobulin Class Switching===
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| *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.
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| *Naïve mature B cells produce both IgM and IgD, which are the first two heavy chain segments in the immunoglobulin locus.
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| **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.
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| **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).<ref name="pmid12884279">{{cite journal| author=Durandy A| title=Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation. | journal=Eur J Immunol | year= 2003 | volume= 33 | issue= 8 | pages= 2069-73 | pmid=12884279 | doi=10.1002/eji.200324133 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12884279 }} </ref>
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| *Class switching occurs by a mechanism called class switch recombination (CSR) binding.
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| **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.
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| **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.
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| **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.<ref name="pmid15496946">{{cite journal| author=Casali P, Zan H| title=Class switching and Myc translocation: how does DNA break? | journal=Nat Immunol | year= 2004 | volume= 5 | issue= 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><ref name="pmid12884279">{{cite journal| author=Durandy A| title=Activation-induced cytidine deaminase: a dual role in class-switch recombination and somatic hypermutation. | journal=Eur J Immunol | year= 2003 | volume= 33 | issue= 8 | pages= 2069-73 | pmid=12884279 | doi=10.1002/eji.200324133 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12884279 }} </ref>= 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>
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| **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.
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| **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.<ref name="pmid16793349">{{cite journal| author=Lieber MR, Yu K, Raghavan SC| title=Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. | journal=DNA Repair (Amst) | year= 2006 | volume= 5 | issue= 9-10 | pages= 1234-45 | pmid=16793349 | doi=10.1016/j.dnarep.2006.05.013 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16793349 }} </ref>
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| **In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins.<ref name="pmid17713479">{{cite journal| author=Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M et al.| title=IgH class switching and translocations use a robust non-classical end-joining pathway. | journal=Nature | year= 2007 | volume= 449 | issue= 7161 | pages= 478-82 | pmid=17713479 | doi=10.1038/nature06020 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17713479 }} </ref>
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| <gallery>
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| Image:Class_switch_recombination.png|Mechanism of class-switch recombination that allows isotype switching in activated B cells<ref>Immunoglobulin class switching. Wikipedia. https://en.wikipedia.org/wiki/Immunoglobulin_class_switching. AccessedonFebruary 29, 2016.</ref>
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| </gallery>
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| ===Type 1 hypergammaglobulinemia===
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| *A mutation in the Tumor Necrosis Factor Super Family member 5 (TNFSF5) gene, which normally encodes CD40 ligand is involved in the pathogenesis of type 1 hypergammaglobulinemia.
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| *Type 1 hypergammaglobulinemia is transmitted in x-linked recessive pattern.
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| mutation in the Tumor Necrosis Factor Super Family member 5 (TNFSF5) gene, which codes for CD40 ligand
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| ==Epidemiology and Demographics==
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| ===Incidence==
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| *The incidence of X-linked hyper-IgM syndrome is approximately [number range] per 100,000 individuals worldwide.
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| *Symptoms of type 1 hyper-IgM immunodeficiency include:
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |