Glomerulonephritis induced by human IgMK-IgG cryoglobulins in mice.
BACKGROUND
Human cryoglobulinemia is sometimes associated with glomerulonephritis (GN) due to deposition of cryoglobulins (cryos). To see whether human cryos can induce GN in mice and to study time-related changes of glomerular lesions and possible factors of cryos' nephritogenicity, we developed an experimental passive model of cryoglobulinemic GN.


METHODS
Two cryos IgMk-IgG from 2 patients with active GN (OLD and SOR), 2 cryos IgMk-IgG (TAC and GRO) and 1 IgM lambda (CHI) from 3 patients without GN were purified, solubilized at 37 degrees C and injected intravenously into BALB/c mice, 4 mg, twice a day. To study the possible factors of cryo nephritogenicity, we analyzed: (a) the presence, amount, and size of complexed IgMk-IgG at 37 degrees C by fast flow liquid chromatography; (b) the Cc1 or Lc1 subclass of rheumatoid factors; (c) the isoelectric points of the IgMks; (d) The proportion of IgG subclasses in cryos.


RESULTS
On day 1 from the beginning of intravenous injections, cryos OLD had induced mesangial deposits of human IgM, human IgG, mouse C3 and mesangial hypercellularity. On day 2, phagocytizing cells were found along with massive endoluminal and subendothelial deposits of IgM, IgG, and C3. On day 6, perivascular infiltrates of mononuclear cells were also seen. Cryos SOR induced a similar but milder form of GN. After administration of purified OLD IgMk, OLD IgG, GRO IgMk or GRO IgG, only OLD IgMk was deposited in the mesangium. Analysis of all the cryos revealed that: the amount of complexed IgMk-IgG at 37 degrees C was always less than 1% of cryos; Cc1 and Lc1 idiotypes were not related to the nephritogenicity of cryos, the isoelectric points of IgMks were 4.5 to 5.5 and IgG1 was the prevalent subclass.


CONCLUSIONS
Data demonstrate that human cryos from patients with GN can induce GN in mice that resembles the corresponding human pathology. The affinity of IgMk for glomeruli and the unexpectedly small amounts of IgMk-IgG complexes at 37 degrees C suggest that there is a role of in situ binding in nephritogenicity which is independent of the isoelectric point, rheumatoid factor idiotype, or IgG subclass.
Fornasieri
A
A
Division of Nephrology and Pathology, San Carlo Borromeo Hospital, Milano, Italy.
Li
M
M
Armelloni
S
S
de Septis
C P
CP
Schiaffino
E
E
Sinico
R A
RA
Schmid
C
C
D'Amico
G
G
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000936:Antigen-Antibody Complex; D002853:Chromatography, Liquid; D003450:Cryoglobulins / Q000009:adverse effects* / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects* / Q000032:analysis / Q000276:immunology; D007075:Immunoglobulin M / Q000009:adverse effects* / Q000032:analysis / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000009:adverse effects / Q000032:analysis; D007275:Injections, Intravenous; D007526:Isoelectric Point; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011507:Proteinuria; D012217:Rheumatoid Factor / Q000032:analysis; D013696:Temperature; D013997:Time Factors
D000936:Antigen-Antibody Complex; D003450:Cryoglobulins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D012217:Rheumatoid Factor