Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases

Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases

Bibliographic Details
Main Author: Kitzmiller, Kathryn Jean
Language:English
Published: The Ohio State University / OhioLINK 2009
Subjects:
Complement
Complement Factor H
Mannan Binding Lectin
CFHR3
CFHR1
Systemic Lupus Erythematosus
Antiphospholipid Syndrome
Age-Related Macular Degeneration
Copy Number Variation
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1261493418
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1261493418
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Complement
Complement Factor H
Mannan Binding Lectin
CFHR3
CFHR1
Systemic Lupus Erythematosus
Antiphospholipid Syndrome
Age-Related Macular Degeneration
Copy Number Variation
spellingShingle Complement
Complement Factor H
Mannan Binding Lectin
CFHR3
CFHR1
Systemic Lupus Erythematosus
Antiphospholipid Syndrome
Age-Related Macular Degeneration
Copy Number Variation
Kitzmiller, Kathryn Jean
Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
author Kitzmiller, Kathryn Jean
author_facet Kitzmiller, Kathryn Jean
author_sort Kitzmiller, Kathryn Jean
title Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
title_short Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
title_full Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
title_fullStr Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
title_full_unstemmed Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases
title_sort variation of complement factor h and mannan binding lectin in human systemic and vascular immune-mediated diseases
publisher The Ohio State University / OhioLINK
publishDate 2009
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1261493418
work_keys_str_mv AT kitzmillerkathrynjean variationofcomplementfactorhandmannanbindinglectininhumansystemicandvascularimmunemediateddiseases
_version_ 1719428612526964736
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu12614934182021-08-03T05:58:05Z Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases Kitzmiller, Kathryn Jean Complement Complement Factor H Mannan Binding Lectin CFHR3 CFHR1 Systemic Lupus Erythematosus Antiphospholipid Syndrome Age-Related Macular Degeneration Copy Number Variation <p>Heritable inherent immune diversity among different individuals is characterized by gene copy number variation (CNV) and polymorphisms of coding and non-coding DNA sequences that collectively contribute to quantitative and qualitative diversities of immune proteins. We hypothesize that inherent genetic diversity of the immune system confers a spectrum of intrinsic strengths among individuals of a population to defend against infections, but inflicts different susceptibilities for immune-mediated diseases. As effectors of immune defense, the complement protein cascades engage in self and nonself differentiation and hemostasis. Inherited or acquired complement deficiency predisposes an individual to recurrent infections and compromises immune tolerance leading to diseases such as Systemic Lupus Erythematosus (SLE), Antiphospholipid Syndrome (APS), and Age-Related Macular Degeneration (AMD). Multiple organ involvement and autoantibody production are characteristics of SLE as well as antiphospholipid antibodies (aPL) and thrombosis which also occurs in APS. Vascular and cellular abnormalities of AMD cause elderly vision loss. Factors affecting racial disparity and severity in SLE and AMD are not well understood at present.</p><p>Complement Factor H (CFH) regulates complement activation in plasma and on host cell surfaces to protect against complement-mediated damage. Mannan Binding Lectin (MBL) deficiency associates with increased infection, thrombosis, and autoimmunity. To determine how complement variation contributes to intrinsic immune strength and diversity, we elucidated MBL and CFH variants in healthy subjects of multiple races, and subjects with SLE, APS, and AMD. </p><p>PmeI Pulsed-Field Gel Electrophoresis and TaqI and PshAI-PvuII Restriction Fragment Length Polymorphism-Southern blots revealed the complexity of the CFH gene region. We established a 76-kb CNV of CFHR3 and CFHR1 (CFHR3-R1) present at 0, 1, or 2 copies, and varies among healthy subjects of different races (χ2=181, p=2.28x10-36). Increased CFHR3-R1 deficiency demonstrates a dosage effect for African American SLE risk such that CFHR3-R1 heterozygous deficiency associates with an OR of 1.67 (95% C.I. 1.09-2.61, p=0.03) whereas CFHR3-R1 homozygous deficiency has an OR of 1.94 (95% C.I. 1.12-3.38, p=0.02). Higher copy numbers of CFHR3-R1, as determined by real-time PCR in European subjects, associates with neovascular AMD (χ2=6.8; p=0.03). CFHR3-R1 has a dual role in racial disparity: high copy numbers in European American AMD risk and low copy numbers in African American SLE risk. </p><p>Phenotypic variation of CFH detected by radial immunodiffusion, and functional MBL protein levels detected by ELISA, enable the investigation of their role in SLE and APS. Subjects with aPL-associated SLE with thrombosis have reduced protein levels of CFH and MBL compared to aPL-only subjects (CFH: 48.9±9.7 vs 54.5±15.4 mg/dL, p=0.001; MBL: 0.114 ± 0.128 vs 0.173 ± 0.192 mg/dL, p=0.0041). Multiple promoter polymorphisms and exon1 variants in MBL correlate with quantitative variations of functional MBL levels among SLE cases. </p><p>In conclusion, quantitative and qualitative variation of CFH and MBL contribute to immune-mediated, human systemic and vascular diseases. Low CFHR3-R1 copy number is a significant risk factor for African American SLE. Identification of subjects at risk or with severe disease manifestations can lead to more accurate diagnoses and reduced disease severity through precautionary intervention.</p> 2009 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1261493418 http://rave.ohiolink.edu/etdc/view?acc_num=osu1261493418 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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