Download Nephropathy and Immunology

Immunologic mechanisms of renal
diseases
Chen weilin，PH.D
Institute of Immunology, ZJU
Email：[email protected]
Antigens
• The cause of immunologically mediated
renal disease is antigenic triggering of an
immune reaction.
• The list of associated antigens is extensive
and continually expanding. These antigens
are categorized as renal or non-renal and as
self or foreign .
• The causative antigen is often unknown.
ANTIGENS ASSOCIATED WITH
IMMUNOLOGICALLY MEDIATED RENAL DISEASE
Antigens
• To cause immunologically mediated renal
disease, an antigen must localize to the kidney
and trigger a local immune inflammatory
response.
• Renal antigens are inherently localized, being
constituent proteins of the kidney.
• Non-renal antigens require a mechanism for
depositing in the kidney.
Immunologic mechanisms of renal
diseases
•
•
•
•
•
•
Type I hypersensitivity (IgE)
Type II hypersensitivity (Cytotoxic Antibody-mediated )
Type III hypersensitivity (Immune Complex-mediated )
Cell-mediated immunity (CD4+,CD8+ T)
Complement activation
Immune hereditary factors (HLA)
Type II hypersensitivity
Ags on the surface of target cells
↓
body→IgG, IgM
↓
1. damage the target cell
1) activation of complement
2) opsonization FcR C3bR
3) ADCC
2. target cell dysfunction
Cytotoxic Antibody-mediated Renal Disease
• Prototype: Anti-GBM disease (Goodpasture's
disease)
• Renal damage is caused by linear deposition of
antibody specific for type IV collagen of the GBM.
The antibody attaches to its antigen and activates
the complement.
• Cytotoxic antibody localizes along the GBM in a
linear pattern with C.
Type III hypersensitivity
Ag→body→IgG, IgM, IgA
↓
immune complexes (IC)
↓
soluble IC
↓
ICs are deposited from the circulation
into vascular basement membranes
①↓
② ↓FcR
activation of complement plat. and basophils
↓
C3a, C5a →mast cell → release of vasoactive amines
↓
basophils
③ Neutrophils
vasodilation
↓
lysosomal
edema
enzymes→damage the tissue
Immune Complex-mediated Renal Disease
• Planted antigen attracts its antibody from the circulation, and a local immune
complex is formed.
• Immune complex localizes in the mesangium, glomerular capillary wall, or renal
interstitium as a lumpy-bumpy pattern.
• Small immune complexes are less likely to be deposited, and large immune
complexes are preferentially removed by RES minimizing localization in the kidney.
• As circulating immune complexes are formed and antibody production increases,
the size of the circulating immune complex increases:
– removal from the circulation by RES cells or
– localization in the mesangium or glomerular capillary wall.
• Various endogenous and exogenous substances may function as antigen in immune
complex formation.
– endogenous nuclear proteins in DNA-anti-DNA IC in lupus nephritis,
streptococcal cell wall antigens in post-streptococcal glomerulonephritis.
IMMUNE COMPLEX GLOMERULAR DISEASE
• Most patients with lupus nephritis have an immune
complex-mediated glomerular disease
• The standard classification divides these disorders
into five different patterns in which (type I)
represents no disease
–
–
–
–
Mesangial (type II)
Focal proliferative (type III)
Diffuse proliferative (type IV)
Membranous (type V)
Renal manifestations of SLE
• Renal involvement is common in SLE
• An abnormal urinalysis is present in approximately
50% of patients at the time of diagnosis and
eventually develops in more than 75 percent of cases
• The most frequently observed abnormality is
– proteinuria (80 %)
– 40% have hematuria and/or pyuria sometime during the
course of their illness
‘Bumpy’ appearance
of immune complexes
deposited in the
glomerulus in SLE
LUPUS NEPHROPATHY
ACUTE NEPHRITIC SYNDROME
(Acute Glomerulonephritis; Postinfectious Glomerulonephritis)
• The prototype of an acute nephritic syndrome is
poststreptococcal glomerulonephritis (PSGN) due to infection
with certain nephritogenic strains of group A -hemolytic
streptococci, such as type 12 (associated with pharyngitis) and
type 49 (associated with impetigo).
• Immunofluorescence microscopy usually shows immune
complex deposition with IgG and C in a granular pattern.
• The presenting manifestations range from asymptomatic
hematuria (in about 50%) and mild proteinuria to full-blown
nephritis with gross or microscopic hematuria proteinuria,
oliguria, edema, hypertension, and renal insufficiency.
IgA NEPHROPATHY
•Berger's disease is now used to describe any idiopathic IgA nephropathy
•Patients have gross or microscopic hematuria, often with high blood
pressure. The disease usually runs a chronic, slowly progressive course
•Mesangial and focal-segmental proliferation and sclerosis may be seen
by light microscopy. In bad cases, crescents develop.
•Immunofluorescence shows IgA deposited in the mesangium (often with
IgG, IgM, and/or C3, but no C4, i.e., the alternate pathway of complement
is being activated.)
•Serum IgA is often elevated, and IgA-containing immune complexes are
often demonstrable, whether or not there is some primary disease to
explain their presence
Cell-mediated Renal Disease
• The prototype is the renal transplant.
• In nearly all non twin transplants, the kidney presents nonself
antigens that trigger an immune (predominantly cellmediated) response.
• If the host has been presensitized to antigens of the renal
graft, transplantation may trigger hyperacute rejection ,
resulting in acute renal ischemia, infarction, and transplant
loss.
• Cell-mediated renal disease appears to play a part in chronic
poststreptococcal glomerulonephritis (PSGN). Lymphocytes
stimulated by exposure to streptococcal wall antigens may
cross-react with renal glomerular antigens, resulting in
progressive cell death and sclerosis of the renal parenchyma.
Mechanisms of graft rejection
IL2, TNF, IFN(
TNF, NO2
Inflammation
IL2, IL4, IL5
IL2,
IFN(
lysis
ADCC
lysis
rejection
Complement activation
Alternative pathway ：C3
MPGN：Ⅰ--- C3 deposit、antibody
Ⅱ--- dense deposit
Ⅲ--- both above
Immune hereditary factors
PSGN has been associated with HLA-B12
IgA nephropathy with HLA-B35 and HLA-DR4
Anti-GBM or Goodpasture's syndrome with HLA-DR2
IMN（idiopathic membeanous nephropathy）with
HLA- II（DR3、DR2、DQ2、DQ1）
Minmal change nephrosis with HLA-DR7、DR9
Diagnosis
• Renal biopsy and light microscopic examination of stained
tissue provide the best method for diagnosing
immunologically mediated renal disease, assessing prognosis,
and selecting treatment.
• Iimmunofluorescence microscopy using fluorescein-labeled
specific antibodies often is also helpful in characterizing the
type and location of immune components in the kidney.
• The type and pattern of C deposition help diagnosis. C
deposition usually follows the pattern of immune complex or
immunoglobulin deposition or both. However, C3 deposition
in the absence of immunoglobulin, Clq, or C4 deposition may
occur via alternative pathway activation in type II MPGN..
Urinalysis
• Examining the urine for protein and formed elements is often
useful.
– Nephrotic syndrome is present in virtually all forms of
immunologically mediated renal disease.
– Abundant protein and frequently lipid-laden modified
tubular epithelial cells are found in the urine.
– Nephrotic-range proteinuria usually suggests an underlying
immune mechanism, although nephrotic syndrome may
occur in nonimmune renal disease (eg, diabetes mellitus).
• Injury resulting in necrosis, as in acute cytotoxic-type injury of
anti-GBM disease, causes significant hematuria.
• Immune complex-type injury is associated with hematuria and
RBC casts..
• MPGN and membranous glomerulonephritis are associated
with significant proteinuria; MPGN usually produces
hematuria, but membranous glomerulonephritis rarely does.
Minimal-change
disease
and
focal
sclerosing
glomerulonephritis may produce only proteinuria.
Serologic Analyses
• Detect
– cytotoxic antibodies in type II renal disease (eg, anti-GBM antibodies, anti-HLA
antibodies).
– CIC may be found in various immune complex-mediated renal diseases.
– Circulating ANCA can be detected in ANCA-mediated renal disease .
• Altered levels of C proteins often differentiate types of immunologically
mediated renal disease.
– When alternative pathway activation predominates (eg, in MPGN and
frequently PSGN), C consumption begins with activation of C3; thus, early
components of C (Clq, C4, and C2) are not depressed.
– In classic pathway activation (eg, in SLE), consumption begins with the early
components, which are thereby depressed.
– The presence of C3 nephritic factor with depressed C3 but normal Clq, C4,
and C2 is virtually diagnostic of MPGN with alternative pathway activation.
• Other helpful serologic analyses include:
– rising antibody titers to streptococcal antigens in PSGN.
– Other postinfective glomerulonephritides eg, a positive test for syphilis,
hepatitis-associated antigen, or rising antibody titers to other infective
organisms..
Histocompatibility testing
• May help diagnose some forms of
immunologically mediated renal disease. For
example,
– PSGN has been associated with HLA-B12,
– IgA nephropathy with HLA-B35 and HLA-DR4, and
– Anti-GBM or Goodpasture's syndrome with HLADR2.