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NDT Advance Access originally published online on April 27, 2006
Nephrology Dialysis Transplantation 2006 21(9):2589-2595; doi:10.1093/ndt/gfl210
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition

Naofumi Imai1, Shinichi Nishi3, Bassam Alchi1, Mitsuhiro Ueno1, Sachiko Fukase1, Masaaki Arakawa1, Kazuhide Saito2, Kota Takahashi2 and Fumitake Gejyo1

1 Division of Clinical Nephrology and Rheumatology, 2 Division of Urology, Niigata University Graduate School of Medical and Dental Sciences and 3 Blood Purification Center, Niigata University Hospital, Niigata, Japan

Correspondence and offprint requests to: Naofumi Imai, Asahimachi-Dori 1-757, Niigata City, 951-8510 Japan. Email: imain{at}med.niigata-u.ac.jp



   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Complement 4d (C4d) deposition in the peritubular capillary (PTC) in the kidney allograft is a useful diagnostic marker for humoral rejection. C4d is produced not only by the classical pathway but also by the lectin pathway of the complement activation cascade. We have recently reported the in situ role of the later phase of the complement cascade in renal allografts with C4d deposition; however, the initial process prior to C4d deposition is yet to be resolved.

Methods. To clarify the early phases of the complement activation cascade, we evaluated the deposition of initial proteins of the above two pathways; IgG, IgM, mannose-binding lectin (MBL), H-ficolin, L-ficolin, MBL-associated serine protease (MASP)-1 and MASP-2 in kidney allografts with PTC C4d deposition.

Results. Sixty kidney allograft specimens were divided into two groups on the basis of the presence of C4d deposition in PTC. The C4d-positive group (n = 18) included nine ABO-identical and nine ABO-incompatible cases, and the C4d-negative group (n = 42) had 34 ABO-identical and eight ABO-compatible (but not identical) cases. In the C4d-positive group, 16 of 18 cases showed diffuse H-ficolin and IgM deposition in PTC. In contrast, H-ficolin and IgM were not detected in PTC in the C4d-negative group. Other initial proteins were not detected in all cases.

Conclusions. Our study suggested for the first time that the lectin pathway activated by H-ficolin may be involved in C4d deposition on PTC in the kidney allograft.

Keywords: C4d; ficolin; kidney allograft; lectin pathway; peritubular capillary; rejection



   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Complement 4d (C4d) frequently gets deposited along the capillary walls in solid organ allografts undergoing acute rejection, particularly in those with humoral rejection. This phenomenon has been documented in the kidney [1], heart [2], lung [3] and liver [4]. However, the exact mechanism of C4d deposition has not been established.

We have recently reported the in situ role of the complement regulatory factor of the later phase of the complement cascade, CD59, in renal allografts with C4d deposition in the peritubular capillary (PTC) [5]. However, the initial processes of C4d deposition in the renal allograft has yet to be resolved. In general, C4d is produced from two distinct pathways of the complement cascade; the classical pathway and the lectin pathway (Figure 1). The classical pathway is triggered by the binding of C1q to immune complexes containing immunoglobulin G (IgG) and/or immunoglobulin M (IgM). The lectin pathway involves carbohydrate recognition by three kinds of pattern-recognition receptors; mannose-binding lectin (MBL), H-ficolin (Hakata antigen) and L-ficolin, and the subsequent activation of associated unique enzymes that are known as MBL-associated serine protease (MASP)-1 and MASP-2 [6,7]. In the present study, we aimed to find the histological evidence for the initial activation of both the classical and lectin pathways in kidney allografts with C4d deposition in PTC.


Figure 1
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  		Fig. 1. The three pathways of the complement cascade. C4d is produced from two pathways, the classical and the lectin pathways, but not from the alternative pathway. The initiators of the lectin pathway consist of three lectins, MBL, H-ficolin and L-ficolin that bind to cell surface carbohydrates. These lectins work with MASP-1 and MASP-2. The classical pathway is initiated by the binding of C1q to antibodies in immune complexes. C1q also has two sorts of associated serine protease, C1r and C1s. C4 is degraded by MASP-2 or C1s to form C4b and then C4d.

 


   Materials and methods
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 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Patients and biopsies
A total of 108 kidney graft biopsies from 82 recipients were performed at Niigata University Hospital over a five-year period (between July 2000 and June 2005). Twenty recipients underwent graft biopsies more than one (total 46 biopsies). In those cases, the last biopsy from each recipient was adopted whereas the other 26 biopsies were excluded from the study. Twenty-two biopsies were not available because frozen tissues were utilized to assist the light microscopic examination when paraffin specimens were inadequate. The remaining 60 biopsies with adequate frozen tissue available for immunohistochemical examinations described subsequently were included in this study. Forty-eight of the studied biopsies were episode graft biopsies obtained for an elevated serum creatinine and/or urinary protein levels, while the remaining 12 were non-episode protocol biopsies. Of the transplanted patients 39 were males and 21 females, aged 38.4 ± 12.3 years. Fifty-two transplants were from living donors and the other eight were cadaveric, and the living transplants included nine ABO-incompatible and eight ABO-compatible, but not identical cases. Renal allograft specimens were divided into two groups based on whether or not C4d deposition is diffusely detected on PTC by immunohistochemical examination. All biopsies were obtained using a 16-gauge Biopty Gun needle (Bard Electrophysiology, Lowell, USA) with ultrasound guidance, after obtaining an informed consent from the patients. Clinical data were gathered from our patient and pathology databases and review of medical records (e.g. age, blood pressure, ABO-blood type, human leukocyte antigen (HLA) typing, warm ischaemic time and total ischaemic time). Serum and urine laboratory data [e.g. urinary protein, blood urea nitrogen (BUN), creatinine, uric acid, serum proteins and anti-ABO antibody titre] were measured at the time of biopsy by the routine hospital methods.

Histological method
For light microscopy, tissues were fixed in 10% buffered formalin and embedded in paraffin. Thin tissue sections were stained with haematoxylin and eosin, periodic acid Schiff, periodic acid methenamine (PAM) and PAM–Masson stains, and evaluated according to the standardized criteria of Banff working classification of kidney transplant pathology. For immunofluorescence study, tissue specimens were immersed in OCT compound (MILES, Elkhart, USA) and frozen in a dry ice–acetone mix. Serial sections of fresh tissue were stained by the following techniques. For direct immunostaining, they were fixed in cold acetone for 10 min and washed with 50 mM Tris-HCl buffer at pH 7.6 for 5 min and subsequently incubated with fluorescin isothiocynate-conjugated rabbit anti-human IgG (1:250), IgM (1:50) and C1q (1:50) polyclonal antibodies (DAKO, Kyoto, Japan) for 1 h at room temperature. For indirect staining, the frozen sections were hydrated in Tris-HCl buffer for 5 min and incubated with monoclonal antibodies against human C4d (A213, Quidel Corporation, San Diego, USA, 1:100), MBL (3E7, Hycult Biotechnology, Uden, Netherlands, 1:50), H-ficolin (4H5, Hycult Biotechnology, Uden, Netherlands, 1:50), L-ficolin (GN4, Hycult Biotechnology, Uden, Netherlands, 1:50), MASP-1 (1E2, Hycult Biotechnology, Uden, Netherlands, 1:50) and polyclonal goat anti-human MASP-2 antibody (N-20, Santa Cruz Biotechnology, Santa Cruz, USA, 1:50) overnight at 4 °C. The specificity of the monoclonal primary antibodies against specific human protein has been characterized by western blot analysis [8–12]. The specificity of the anti-human MASP-2 antibody was confirmed by western blotting (manufacturer information). After washing with Tris-HCl buffer for 10 min, a secondary fluorescin isothiocynate-labelled anti-mouse polyclonal goat (DAKO, Kyoto, Japan, 1:40) or anti-goat polyclonal rabbit (Bethyl Laboratories, Montgomery, USA, 1:100) antibody was added for 1 h at room temperature. The sections were washed again, coverslipped with 50% glycerine and observed under a fluorescence microscope (Carl Zeiss, Tokyo, Japan). We considered a case to be positive for an individual antibody when the immunofluorescence signal was seen diffusely along the PTC, whereas a focally positive finding was considered negative. Kidney biopsy specimens from three patients with membranous type systemic lupus erythematosus nephritis were used as positive staining controls. When primary antibody was replaced with 1% bovine serum albumin in Tris-HCl buffer (negative control), the lack of staining verified the specificity of the antibody. To clarify whether IgM and H-ficolin are on different capillaries and which of the two are better associated with C4d, we conducted double stains for IgM vs H-ficolin vs C4d using the following antibodies: rabbit anti-human C4d polyclonal antibody (C4dpAb, Biomedica, Vienna, Austria, 1:50); tetramethylrhodamine isothiocyanate isomer R (TRITC)-labelled swine anti-rabbit second antibody (DAKO, Kyoto, Japan, 1:40) for the H-ficolin vs C4d double stain; and TRITC-labelled rabbit anti-mouse second antibody (DAKO, Kyoto, Japan, 1:40) for IgM vs C4d double stain. The detailed characterization of polyclonal anti-C4d antibody has been described elsewhere [13].

Statistical method
We used the unpaired t-test (Student's t-test) for the comparison of clinical and laboratory data. P-values <0.05 were used as the criteria of statistically significant differences.



   Results
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 Abstract
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 Materials and methods
 Results
Discussion
 References
 
Eighteen of the 60 cases showed diffuse C4d deposition in PTC, whereas the other 42 cases were either negative or focally positive for C4d. Tables 1 and 2 show the clinical profile of patients in the C4d-positive and -negative groups, respectively. Notably, all of the ABO-incompatible cases were in the C4d-positive group, and that C4d deposition in the PTC was seen in five cases without morphological features of rejection. Significantly raised anti-ABO antibody titre was detected at the biopsy time in patients 11 and 15. Table 3 shows the immunohistochemical findings in the C4d-positive group. In 14 cases, both IgM and H-ficolin were diffusely positive along the PTC as illustrated in Figure 2, and in the other four cases either IgM or H-ficolin was detected. C4d, IgM and H-ficolin were also found in glomeruli and arteries. IgG, C1q, MBL, L-ficolin, MASP-1 and MASP-2 did not react to the PTC (Figure 3). On the other hand, in the C4d-negative group, the whole panel of anti-sera produces a negative result (data not shown). As a reference, 16 available pre-index biopsy specimens from the patients who had multiple graft biopsies, showed consistent immunohistochemical findings with that of the last biopsy. On double stains, as described in the methods, the immunofluorescence signals using antibodies against IgM, H-focolin and C4d colocalized to the same PTC (data not shown).


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  		Table 1. Profile of C4d-positive patients

 

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  		Table 2. Profile of C4d-negative group

 

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  		Table 3. Immunohistochemical findings of C4d-positive group

 

Figure 2
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  		Fig. 2. Typical immunohistochemical positive findings in serial sections of a C4d-positive case (case 11). Upper panel photographs are at low magnification (original magnification 50x). (A) C4d diffusely deposited on PTC. (B) H-ficolin strongly found along the PTC with a weak signal in the interstitium. (C) IgM was diffusely positive on PTC and weakly positive in the interstitium. The lower panel photographs demonstrate the linear reaction of PTC to antibodies against (D) C4d, (E) H-ficolin and (F) IgM (similar arrows or arrowheads show the same PTC).

 

Figure 3
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  		Fig. 3. Typical immunohistochemical negative findings in a C4d-positve case (case 11). (A) IgG was negative on the PTC, but weakly positive in the interstitium. (B) Anti-C1q, (C) MBL, (D) L-ficolin, (E) MASP-1 and (F) MASP-2 (original magnification 50x).

 
Table 4 compares the clinical and laboratory data between C4d-positive and -negative groups. The mean BUN, serum creatinine, uric acid and serum amyloid A levels in the C4d-positive group were significantly higher than those in the C4d-negative group. This is simply because 17 of 18 (94%) biopsies in the C4d-positive group were episode biopsies.


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  		Table 4. Clinical data at the time of biopsy

 


   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The pathological phenomenon of C4d deposition into PTC was first reported by Feucht et al. [1] as a histological marker suggesting humoral rejection. Since the molecule of C4d has a durable and covalent binding character to the cell surface, the detection of C4d was supposed to be evidence of immunological activation in situ. It has been reported that 43–90% of the C4d-positive recipients had donor-specific alloantibody, usually against major histocompatibility complex (MHC) class I and/or class II [14–17], thereby C4d deposition in PTC was considered to be a reliable marker for humoral rejection.

In humoral rejection, it is believed that some alloantigens expressing on vascular components become the target antigens and introduce the activation of the complement cascade. Although PTC C4d deposition is apparently a result of an activated complement cascade, its precise mechanism is still unclear. Among the three known complement pathways, activation of the classical pathway and/or lectin pathway can result in the formation of C4d. In a previous study, the detection of C4d along the PTC was not accompanied by any deposition of immunoglobulins or other initiators of the classical complement pathway even in the presence of circulating donor-specific antibodies [18]. One reason for the lack of immunohistochemical staining signals is believed to be the rapid shedding and endocytosis of immunoglobulins and activated complement factors from endothelial cell surfaces, and thus is not evidence against the presence of circulating antibodies and the activation of the classical complement cascade. In our study, 16 of 18 (88.9%) C4d-positive cases had H-ficolin on PTC, indicating frequent activation of the lectin pathway in the setting of C4d positivity. The reason behind the high incidence of IgM deposits along PTC in our series (88.9%) is not clear, but may be in part explained by the ABO-incompatible grafting.

C1q activates the classical complement pathway and subsequently IgG and/or IgM in the antigen–antibody complexes, working as ligands for C1q and may react with MHC class I and/or class II antigens in the kidney allograft. In a previous report, IgM (87.5%) and IgG (37.5%) have been found with C4d on PTC in the perioperative graft biopsies in ABO-incompatible renal transplantation [19]. Onitsuka et al. [20] reported that C4d deposition in PTC was seen in 10 of 19 patients with ABO-incompatible acute rejection. This high frequency of C4d deposition on PTC was thought to be correlated with non-HLA anti-donor antibodies including anti-A or anti-B antibodies. In our study, all cases of ABO-incompatible transplants showed both C4d and H-ficolin deposition in PTC suggesting that ABO-blood type antigens may function as ligands for H-ficolin. However, only two of nine patients (22.2%) with ABO-incompatible transplants had significantly raised anti-ABO antibody titre >1:16. This may be because of the accommodation phenomenon in which antibodies persisting in the blood after pre-transplant antibody removal become attached to the blood antigens on the vascular endothelium of the graft leading to a decline in anti-ABO antibody titres immediately after transplantation [21].

The lectin pathway is a newly discovered complement activation pathway [22]. It activates C4 without immunoglobulin or C1q. MBL was initially thought to be the only trigger of lectin pathway activation, a process that involves the activation of its associated MASP-1 and MASP-2. However, recently H-ficolin and L-ficolin were recognized as other initiative lectins in this pathway. Similar to a previous study [23], we could not detect MBL, MASP-1 and MASP-2 in the kidney allograft biopsy with C4d deposition in PTC, though the presence of H-ficolin indicates a possible role of the lectin pathway in C4d deposition.

Lectins are specific carbohydrate-binding proteins. MBL, H-ficolin and L-ficolin commonly bind to terminal N-acetyl-glucosamine (GlcNAc) [7,24]. MBL can also react with D-mannose [24] and H-ficolin with N-acetyl-galactosamine (GalNAc) [7]. The ABO-blood type antigens are carbohydrate antigens that express on the vascular endothelial cell surfaces. The H-chain is the common basic structure of all blood types. B-antigen has a terminal galactose and A-antigen has a terminal GalNAc connecting to the fucose of H-chain. The GalNAc terminal of A-antigen may react to H-ficolin, however, the PTC of B-incompatible allografts and blood type-matched allografts also showed a positive reaction to H-ficolin in the present study. Therefore, the ligands of H-ficolin may not be restricted to the carbohydrate ligands of ABO-blood types.

Interestingly, C4d deposition in PTC has been described as a magic marker in the transplantation field [25]. Although, C4d deposition in PTC is a robust immunohistochemical marker for humoral rejection, it can also be seen in grafts with no histological evidence of rejection, particularly in ABO-incompatible grafts. Moreover, diffuse C4d deposition in PTC in non-indicated protocol biopsies from renal allografts was reported in a recent multicentre study [26]. It is therefore questionable, whether or not the mechanism of C4d deposition in various conditions is uniform.

In conclusion, the present study indicated for the first time that the activated lectin pathway by H-ficolin may be involved in the deposition of C4d on PTC in allograft kidney.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 10. 7.05
Accepted in revised form: 24. 3.06


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