Quaternary Epitopes of α345(IV) Collagen Initiate Alport Post-Transplant Anti-GBM Nephritis

Abstract

Alport post-transplant nephritis (APTN) is an aggressive form of anti-glomerular basement membrane disease that targets the allograft in transplanted patients with X-linked Alport syndrome. Alloantibodies develop against the NC1 domain of a5(IV) collagen, which occurs in normal kidneys, including renal allografts, forming distinct a345(IV) and a1256(IV) networks. Here, we studied the roles of these networks as antigens inciting alloimmunity and as targets of nephritogenic alloantibodies in APTN. We found that patients with APTN, but not those without nephritis, produce two kinds of alloantibodies against allogeneic collagen IV. Some alloantibodies targeted alloepitopes within a5NC1 monomers, shared by a345NC1 and a1256NC1 hexamers. Other alloantibodies specifically targeted alloepitopes that depended on the quaternary structure of a345NC1 hexamers. In Col4a5-null mice, immunization with native forms of allogeneic collagen IV exclusively elicited antibodies to quaternary a345NC1 alloepitopes, whereas alloimmunogens lacking native quaternary structure elicited antibodies to shared a5NC1 alloepitopes. These results imply that quaternary epitopes within a345NC1 hexamers may initiate alloimmune responses after transplant in X-linked Alport patients. Thus, a345NC1 hexamers are the culprit alloantigen and primary target of all alloantibodies mediating APTN, whereas a1256NC1 hexamers become secondary targets of antia5NC1 alloantibodies. Reliable detection of alloantibodies by immunoassays using a345NC1 hexamers may improve outcomes by facilitating early, accurate diagnosis.

Multidisciplinary and multidimensional approaches to transplantation in children with rare genetic kidney diseases

“…73 De novo anti-GBM antibody disease (also referred to as Alport post-transplant nephritis) develops in approximately 3% of transplanted males. 82,83 Patients with Alport syndrome require supportive measures for hearing loss (eg, hearing aids) and ocular impairment. Close collaboration with ophthalmology, otolaryngology, or ear-nose-throat (ENT) specialists, audiologists, as well as, school personnel is critical to improve clinical care and quality of life.…”

“…De novo anti‐GBM antibody disease (also referred to as Alport post‐transplant nephritis) develops in approximately 3% of transplanted males 82,83 …”

Alport syndrome: a rare cause of uraemia

“…It especially occurs in male patients of AS who present with ESRD and deafness early (within the second decade of life) and have detectable circulating anti-GBM antibodies16 due to absolute lack of the normal ‘Alport antigen’ 17. A very low incidence of clinical anti-GBM disease18 is seen in female patients as they have one normal allele due to their inherent heterozygosity of the mutational chromosomal defect.…”

IgG4-Restricted Anti–Glomerular Basement Membrane Autoantibodies Targeting Quaternary Epitopes of Native α345(IV) Collagen

“…[2][3][4][5] In contrast, Alport alloantibodies have decreased reactivity toward dissociated a345NC1 hexamers because some alloantibodies target alloepitopes dependent on the native quaternary structure of a345NC1 hexamers. [5][6][7] Exceptions to this pattern of reactivity have begun to emerge. IgG4-restricted anti-GBM autoantibodies binding specifically to native a345NC1 hexamers but not to a3NC1 or a5NC1 monomers have been identified in a patient with mild glomerulonephritis.…”