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1.
J Immunol ; 205(6): 1535-1539, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32769119

ABSTRACT

C8α-γ deficiency was examined in four unrelated African Americans. Two individuals were compound heterozygotes for a previously reported point mutation in exon 9. mRNA from the remaining six C8A alleles contained a 10 nt insertion between nt 992 and 993 corresponding to the junction between exons 6 and 7. This suggested that C8α-γ deficiency in these individuals was caused by a splicing defect. Genomic sequencing revealed a G→A point mutation in intron 6, upstream of the exon 7 acceptor site. This mutation converts a GG to an AG, generates a consensus 3' splice site that shifts the reading frame, and creates a premature stop codon downstream. To verify that the point mutation caused a splicing defect, we tested wild-type and mutant mRNA substrates, containing 333 nt of the C8α intron 6/exon 7 boundary, in an in vitro splicing assay. This assay generated spliced RNA containing the 10 bp insertion observed in the C8α mRNA of affected patients. In addition, in mutant RNA substrates, the new 3' splice site was preferentially recognized compared with wild-type. Preferential selection of the mutant splice site likely reflects its positioning adjacent to a polypyrimidine tract that is stronger than that adjacent to the wild-type site. In summary, we have identified a G→A mutation in intron 6 of C8A as a predominant cause of C8α-γ deficiency in African Americans. This mutation creates a new and preferred 3' splice site, results in a 10 nt insertion in mRNA, shifts the reading frame, and produces a premature stop codon downstream.


Subject(s)
Black or African American , Complement C8/genetics , Immunologic Deficiency Syndromes/genetics , Point Mutation/genetics , Protein Splicing/genetics , RNA Splice Sites/genetics , RNA, Messenger/genetics , Alleles , Genetic Association Studies , Heterozygote , Humans , Sequence Analysis, DNA
3.
Allergy Asthma Proc ; 34(1): 103-7, 2013.
Article in English | MEDLINE | ID: mdl-23406943

ABSTRACT

A 9-year-old African American boy presented with chronic urticaria and progressive spondyloarthritis. Laboratory tests were abnormal for persistently positive antinuclear antibodies and undetectable total hemolytic complement (CH50) despite normal levels of complement C2, C3, and C4. Ultimately, further testing revealed an underlying deficiency in the immune system that may be associated with autoimmune disease and thus have a bearing on the patient's urticaria and spondyloarthritis. This is a unique presentation of a rare disease and underscores the importance of evaluating for systemic disease in the workup of chronic urticaria.


Subject(s)
Joints/immunology , Spondylitis, Ankylosing/diagnosis , Urticaria/diagnosis , Antibodies, Antinuclear/blood , Child , Chronic Disease , Complement Hemolytic Activity Assay , Complement System Proteins/deficiency , Diagnosis, Differential , Disease Progression , Humans , Male , Receptors, IgE/immunology , Serologic Tests , Spondylitis, Ankylosing/etiology , Urticaria/complications
4.
Clin Immunol ; 145(3): 241-50, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23117396

ABSTRACT

C3 deficiency is a rare disorder that leads to recurrent pyogenic infections. Here we describe a previously healthy 18 y/o Caucasian male with severe meningococcal disease. Total hemolytic activity was zero secondary to an undetectable C3. The C3 gene was normal by sequencing. Mixing the patient's serum with normal human serum led to C3 consumption. An IgG autoantibody in the patient's serum was identified that stabilized the classical pathway C3 and C5 convertases, thus preventing decay of these enzyme complexes. This autoantibody is an example of a C4 nephritic factor, with an additional feature of stabilizing the C5 convertase. Previous patients with C4 nephritic factor had membranoproliferative glomerulonephritis. Two years after presentation, this patient's C3 remains undetectable with no evidence of renal disease. We revisit the role of autoantibodies to classical pathway convertases in disease, review the literature on C4-NeF and comment on its detection in the clinical laboratory.


Subject(s)
Autoantibodies/blood , Complement C3 Convertase, Classical Pathway/metabolism , Complement C3/deficiency , Meningococcal Infections/etiology , Adolescent , Complement C3/genetics , Complement C3/immunology , Complement C3 Convertase, Classical Pathway/immunology , Complement C5 Convertase, Classical Pathway/immunology , Complement C5 Convertase, Classical Pathway/metabolism , Complement System Proteins , Enzyme Stability , Humans , Immunoglobulin G/blood , Male , Meningitis, Meningococcal/etiology , Meningitis, Meningococcal/immunology , Meningococcal Infections/immunology , Models, Immunological , Sepsis/etiology , Sepsis/immunology , Sequence Analysis, DNA
5.
Curr Opin Rheumatol ; 24(5): 522-9, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22810363

ABSTRACT

PURPOSE OF REVIEW: This review summarizes the recent advances in complement biology and the evolving understanding of these contributions to the pathophysiology and treatment of predominantly pediatric disease syndromes. RECENT FINDINGS: Identification of lupus patients with complete deficiencies of one of the plasma complement proteins enabled the field to move beyond the notion of complement as a laboratory curiosity. Clinical investigation of the manifestations observed in deficient patients has further defined the biology of the system in normal individuals. Definition of the assembly of the C3 convertases, particularly that of the alternative pathway and its regulation, has led to the appreciation that the complement system includes membrane inhibitors that are every bit as important as those in plasma. The exploration of disease states in which significant complement deposition occurs has moved the field away from consideration of this finding as a bystander effect. Dissection of these syndromes has led to the unanticipated finding of a central role for function-altering mutations in the complement proteins that form or regulate the alternative pathway C3 convertase and has opened the door to new therapeutic approaches. The disease states discussed in the review - pediatric systemic lupus erythematosus, atypical hemolytic uremic syndrome, and the complocentric membranoglomerulopathies - illustrate this evolutionary history of complement biology. SUMMARY: This review emphasizes that both the lack of classical pathway complement activation and excessive activation of the alternative pathway contribute to distinct disease pathogenesis, and emphasizes the critical importance of homeostatic regulation, in both plasma and in tissues, of the system as a whole.


Subject(s)
Complement Activation , Glomerulonephritis, Membranous/immunology , Hemolytic-Uremic Syndrome/immunology , Lupus Erythematosus, Systemic/immunology , Atypical Hemolytic Uremic Syndrome , Child , Complement Activation/genetics , Complement Membrane Attack Complex/immunology , Complement Pathway, Alternative , Complement Pathway, Classical , Glomerulonephritis, Membranoproliferative/immunology , Glomerulonephritis, Membranous/genetics , Hemolytic-Uremic Syndrome/genetics , Humans , Lupus Erythematosus, Systemic/genetics , Mutation , Rheumatic Diseases/immunology
6.
Trans Am Clin Climatol Assoc ; 122: 48-58, 2011.
Article in English | MEDLINE | ID: mdl-21686208

ABSTRACT

Medical education is at a crossroads. Although unique features exist at the undergraduate, graduate, and continuing education levels, shared aspects of all three levels are especially revealing, and form the basis for informed decision-making about the future of medical education.This paper describes some of the internal and external challenges confronting undergraduate medical education. Key internal challenges include the focus on disease to the relative exclusion of behavior, inpatient versus outpatient education, and implications of a faculty whose research is highly focused at the molecular or submolecular level. External factors include the exponential growth in knowledge, associated technologic ("disruptive") innovations, and societal changes. Addressing these challenges requires decisive institutional leadership with an eye to 2020 and beyond--the period in which current matriculants will begin their careers. This paper presents a spiral-model format for a curriculum of medical education, based on disease mechanisms, that addresses many of these challenges and incorporates sound educational principles.


Subject(s)
Curriculum/trends , Education, Medical, Undergraduate/trends , Schools, Medical/trends , Teaching/trends , Education, Medical, Undergraduate/organization & administration , Forecasting , Humans , Leadership , Learning , Models, Educational , Organizational Innovation , Schools, Medical/organization & administration , Teaching/organization & administration , United States
9.
J Clin Immunol ; 23(4): 297-305, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12959222

ABSTRACT

About 25% of C2-deficient homozygotes have increased susceptibility to severe bacterial infections. C2-deficient homozygotes had significantly lower serum levels of IgG2, IgG4, IgD, and Factor B, significantly higher levels of IgA and IgG3 and levels of IgG1 and IgM similar to controls. Type 1 (28 bp deletion in C2 exon 6 on the [HLA-B18, S042, DR2] haplotype or its fragments) and type II (non-type I) C2-deficient patients with increased susceptibility to bacterial infection had significantly lower mean levels of IgG4 (p < 0.04) and IgA (p < 0.01) than those without infections (who had a higher than normal mean IgA level) but similar mean levels of other immunoglobulins and Factor B. Of 13 C2-deficient homozygotes with infections, 85% had IgG4 deficiency, compared with 64% of 25 without infections. IgD deficiency was equally extraordinarily common among infection-prone (50%) and noninfection-prone (70%) homozygous type I C2-deficient patients. IgD deficiency was also common (35%) among 31 type I C2-deficient heterozygotes (with normal or type II haplotypes), but was not found in 5 type II C2-deficient heterozygotes or 1 homozygote. Thus, C2 deficiency itself is associated with many abnormalities in serum immunoglobulin levels, some of which, such as in IgG4 and IgA, may contribute to increased susceptibility to infection. In contrast, IgD deficiency appears not to contribute to increased infections and appears to be a dominant trait determined by a gene or genes on the extended major histocompatibility complex (MHC) haplotype [HLA-B 18, S042, DR2] (but probably not on type II C2-deficient haplotypes) similar to those previously identified on [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3].


Subject(s)
Complement C2/deficiency , Dysgammaglobulinemia/immunology , Infections/etiology , Complement C2/genetics , Complement Factor B/analysis , Disease Susceptibility , Haplotypes , Heterozygote , Homozygote , Humans , IgA Deficiency/immunology , IgG Deficiency/immunology , Immunoglobulin D/deficiency , Immunoglobulins/blood
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