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![(Auto)Antigens and Their Impact on the Evolution of B Cell Receptor IGs of Chronic Lymphocytic Leukemia Subset #4 için kapak resmi (Auto)Antigens and Their Impact on the Evolution of B Cell Receptor IGs of Chronic Lymphocytic Leukemia Subset #4 için kapak resmi](/client/assets/d79c3e4af2b6d196/ctx/images/no_image.png)
(Auto)Antigens and Their Impact on the Evolution of B Cell Receptor IGs of Chronic Lymphocytic Leukemia Subset #4
Başlık:
(Auto)Antigens and Their Impact on the Evolution of B Cell Receptor IGs of Chronic Lymphocytic Leukemia Subset #4
Yazar:
Liu, Yun, author.
ISBN:
9780438058781
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (151 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Nicholas Chiorazzi Committee members: Yousef Al-Abed; Anne M. Davidson; Barbara A. Sherry; Bettie M. Steinberg; Patrick C. Wilson.
Özet:
The selection and transformation of a normal B cell into a leukemic one in chronic lymphocytic leukemia (CLL) is mediated, at least in part, by the structure of the cell's antigen-binding site of the B-cell receptor (BCR) immunoglobulin (IG). A dramatic indication of the role played by BCR is those CLL cases expressing "stereotyped" BCR IGs, characterized by very similar VH CDR3 amino acid sequences often encoded by specific IGHV, IGHD, and IGHJ gene segments. In light of this, collective studies have identified a number of auto- and exo-antigens (non-self-IG antigens) that are recognized by CLL IGs. However, emerging evidences suggest that CLL IGs universally develop the property of self-reactivity (self-IG) which consequently leads to autonomous signaling. To understand the relative roles of these two antigen binding properties in the development and evolution of CLL IG, structure stereotyped IGs from patients falling into subset #4 are used.
Here I show the (auto)antigens recognized by CLL stereotyped subset #4 BCR IGs. Subset #4 IGs react with viable memory as well as naive B lymphocytes, the latter as such represent anti-B-cell autoantibodies. However, the same subset #4 IGs also interact with influenza A viruses, binding to both group 1 and group 2 hemagglutinins. Surprisingly, subset #4 IGs lack reactivity to other autoantigens commonly recognized by IGHV4-34-expressing mAbs, i.e., DNA and I-/i- type antigens, albeit the structural features characteristic of such IGs strongly suggest that such reactivities should prevail.
I have also determined the impact of IG isotype class switching, carried out by the class switch recombination (CSR) mechanism, to BCR specificity and function. Only the class switched versions, i.e. the IgG versions of subset #4 IGs self-associate and consequently induce autonomous signaling. Notably, self-association then, in turn, generates the scaffold of the binding site(s) that can react to viable B cells and influenza viruses. Isotype class switching to IgG also negatively associates with reactivity to DNA and I-/i- type antigens, since the IgM-linked versions of subset #4 variable region binds strongly to DNA as well as I-/i- antigens, implying CSR functioned as a way to reduce autoreactivity.
Finally, somatic mutations impact the binding to viable B cells and influenza A virus differently. Reactivity with viable B-cell surfaces depends on a single somatic mutation "N66D" occurring in the variable domain of the L chain. However, the binding to flu virus largely depends on the somatic mutations on the variable region of the H chain and is closely related to autoreactivity with DNA and I-/i- type antigens. Somatic mutations developing outside of the IGHV4-34 gene dramatically increased binding to flu viruses, whereas the same mutations caused significant reactivity to the autoantigen DNA. To "rescue" this autoreactive clone, somatic mutations, occurring within IGHV4-34 gene were selected, thereby eventually eliminating this autoreactivity. Different to DNA, the somatic mutations on H chain variable domains all lead to the diminished reactivity to I-/i- type antigens.
Together my findings indicate that distinct auto- and exo-antigens collaborate to mediate the positive and negative selection of the structural elements acquired by SHM and CSR that are characteristic of this unique subset of stereotyped BCR IGs. Moreover, my data show that the reactivity of subset #4 IGs with viable B-cell surface and influenza A virus requires the self-association of these IGs and, therefore, strongly suggest that these binding properties is mediated by a non-conventional binding site created by self-associated surface membrane bound IGs.
Notlar:
School code: 1983
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(682854.1) | 682854-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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