Recognition of Human Cytomegalovirus by Human Primary Immunoglobulins Identifies an Innate Foundation to an Adaptive Immune Response

McLean, Gary R.; Olsen, Ole; Watt, Ian N.; Rathanaswami, Palaniswami; Leslie, Kevin B.; Babcook, John S.; Schrader, John W.

doi:10.4049/jimmunol.174.8.4768

Cited by 38 publications

(61 citation statements)

References 47 publications

(52 reference statements)

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“…In the Fab KE5/AD-2S1 complex, as had been seen in the 8F9/AD-2S1 structure (24), many residues encoded by the germline V genes make key contacts with Ag peptide side chains, and affinity maturation serves to support these germline-encoded contacts. A closer inspection of the residues encoded by the L chain V gene IGKV3-11 reveals two key basic and aromatic germline-encoded residues, Arg 91 (L) and Trp 94 (L), which are conserved in all four Fab molecules and make important Ag contacts (10,15,23,24,33,34). The side chain of Arg 91 (L) sits at the base of CDRL3 and CDRH3, forming hydrogen bonds with both the L-rhamnose and AD2-S1 Ags.…”

Section: Discussionmentioning

confidence: 99%

“…With the ability to generate a multitude of possible different Ig molecules (10 6 - 10 8 ), is there any selective advantage in the maintenance and preferential use of certain V genes, and why is a restricted oligoclonal response observed to particular pathogens? It has been speculated that evolutionary pressure from important pathogens could retain certain IgV genes and that IgV genes encode in the germline amino acid residues that contact epitopes on a pathogen (13,14,15). However, two necessary conditions apply.…”

mentioning

confidence: 93%

“…When infected with HCMV, humans can mount a neutralizing Ab response against the gB envelope protein of the virus. Within the gB protein lies a linear epitope, AD-2S1, that neutralizing Abs target, disrupting the ability of the virus to fuse with host cell membranes (15,23). Interestingly, independently originating human mAbs targeting AD-2S1 preferentially use the same pair of IgV genes, IGHV3-30 and IGKV3-11 (15), as those found for the 23F serotype of S. pneumoniae.…”

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confidence: 99%

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Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Bryson

Thomson

Risnes

et al. 2016

The Journal of Immunology

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The human Ab response to certain pathogens is oligoclonal, with preferred IgV genes being used more frequently than others. A pair of such preferred genes, IGVK3-11 and IGVH3-30, contributes to the generation of protective Abs directed against the 23F serotype of the pneumonococcal capsular polysaccharide of Streptococcus pneumoniae and against the AD-2S1 peptide of the gB membrane protein of human CMV. Structural analyses of Fab fragments of mAbs 023.102 and pn132p2C05 in complex with portions of the 23F polysaccharide revealed five germline-encoded residues in contact with the key component, l-rhamnose. In the case of the AD-2S1 peptide, the KE5 Fab fragment complex identified nine germline-encoded contact residues. Two of these germline-encoded residues, Arg91L and Trp94L, contact both the l-rhamnose and the AD-2S1 peptide. Comparison of the respective paratopes that bind to carbohydrate and protein reveals that stochastic diversity in both CDR3 loops alone almost exclusively accounts for their divergent specificity. Combined evolutionary pressure by human CMV and the 23F serotype of S. pneumoniae acted on the IGVK3-11 and IGVH3-30 genes as demonstrated by the multiple germline-encoded amino acids that contact both l-rhamnose and AD-2S1 peptide.

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Section: Discussionmentioning

confidence: 99%

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confidence: 93%

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confidence: 99%

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Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Bryson

Thomson

Risnes

et al. 2016

The Journal of Immunology

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“…mAbs were serially diluted, added to GM-CSF at a concentration of 400 pg/mL, and preincubated at 37°C for 1 h. The mAb/GM-CSF mixtures were added to an equal volume of washed TF-1 cells, 1,000 cells per well, yielding a final concentration of 200 pg/mL GM-CSF. KE5, which is a human mAb IgG1 molecule against human cytomegalovirus, was used as a negative control (56). To control that the mAbs did not inhibit TF-1 cells, the GM-CSF was replaced by a final concentration of 1% (vol/vol) gibbon IL-3-conditioned medium.…”

Section: Methodsmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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“…Antibodies generated to AD-2 are unique, in that they are potently neutralizing antibodies, but approximately only 50% of seropositive individuals generate antibodies to this site [52], which is thought to be due to proximity to the larger more immunogenic AD-1 epitope in the gB structure, which results in antigenic competition during immune responses [51]. Furthermore, human B cells have been shown to perform limited VDJ recombination events that are required for antibodies that target AD-2 [53], whereas there are numerous possibilities for generation of AD-1-specific antibodies. Interestingly, antibodies to AD-2 have been demonstrated to block placental infection of HCMV [54] and may, therefore, be the most critical site for antibodies to target to reduce vertical transmission.…”

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confidence: 99%

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

Manghera

McLean

2016

Future Virol.

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A vaccine for Human cytomegalovirus (HCMV) remains a high priority as complications following infection are observed in immunocompromised individuals and in congenitally infected neonates. Numerous preclinical and clinical studies have investigated vaccine strategies ranging from live attenuated preparations, nucleic acid-based approaches and recombinant delivery systems to subunit vaccines. These have defined the importance of both cell-mediated and humoral immunity to viral gB in the control of HCMV infection. This review will cover clinical trials investigating vaccine approaches that have incorporated gB and discuss the future perspectives of the recombinant gB subunit vaccine for HCMV. BackgroundHuman cytomegalovirus (HCMV) is a ubiquitous pathogen, known to infect all human populations worldwide [1]. It is an enveloped dsDNA virus that is the largest member of the Herpesviridae family that also includes important pathogens, such as HSV-1 and HSV-2, EBV and varicella zoster virus (VZV), all of which are widespread in human populations [2]. The HCMV genome is approximately 230 kbp encoding 200-250 open reading frames, many of which facilitate immune evasion [3]. A recent study of the HCMV genome and translation products has suggested that it may be even more complex than anticipated with regulation of alternate transcripts allowing for numerous polypeptides to be expressed [4]. Transmission of HCMV predominantly occurs via body fluids, such as saliva, blood, urine and breast milk, leading to contact of the mucosal surfaces, primarily infecting epithelial and endothelial cells, followed by dissemination to numerous organs and tissues [5]. HCMV is, therefore, able to infect a wide range of cells including endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, leukocytes and dendritic cells [5,6]. Similarly to other Herpesviridae family members, HCMV is capable of both lytic and latent infections [7], but primary infection and reactivation from latency are often asymptomatic in immunocompetent individuals [8]. HCMV infection and reactivation in both solid organ and hematopoietic stem cell transplant recipients, and fetal exposure in utero poses a major threat. Immunocompromised individuals, including AIDS patients [9,10] and transplant patients [11,12], are at increased risk of both reactivation or reinfection, and primary HCMV infection has serious consequences for the developing fetus in pregnant women [8]. It is estimated that HCMV congenital infection occurs in 0.5-2% of all annual pregnancies [13], and approximately 10% of infants with congenital HCMV infection present with clinical manifestations at birth, such as hearing loss and neurological developmental defects [14]. Additionally, late-onset hearing disorders can occur with both symptomatic and asymptomatic congenital infection, which [17], which may also be effective in treating congenital infections [18]. Based on the widespread prevalence of HCMV, limited treatment options and the potential for significant morbidity, an effective ...

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Recognition of Human Cytomegalovirus by Human Primary Immunoglobulins Identifies an Innate Foundation to an Adaptive Immune Response

Cited by 38 publications

References 47 publications

Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Structures of Preferred Human IgV Genes–Based Protective Antibodies Identify How Conserved Residues Contact Diverse Antigens and Assign Source of Specificity to CDR3 Loop Variation

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Human Cytomegalovirus Vaccination: Progress and Perspectives of Recombinant gB

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