Title: Immunologic mechanisms of renal diseases
1Immunologic mechanisms of renal diseases
- Chen weilin,PH.D
- Institute of Immunology, ZJU
- Emailcwl_at_zju.edu.cn
2Antigens
- 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.
3ANTIGENS ASSOCIATED WITHIMMUNOLOGICALLY MEDIATED
RENAL DISEASE
4Antigens
- 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.
5Immunologic mechanisms of renal diseases
- Type II hypersensitivity (Cytotoxic
Antibody-mediated ) - Type III hypersensitivity (Immune
Complex-mediated ) - Cell-mediated immunity (CD4,CD8 T)
- Abnormal Immune regulation (Ts)
- Immune hereditary factors (HLA)
6Type 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
-
7Cytotoxic 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.
8(No Transcript)
9(No Transcript)
10Type III hypersensitivity
- Ag?body?IgG, IgM, IgA
-
? - immune complexes (IC)
- ?
- soluble IC
- ?
- ICs are deposited from the
circulation - into vascular basement membranes
- ?? ?
?FcR - activation of complement plat. and basophils
- ?
- C3a, C5a ?mast cell ? release of vasoactive
amines - ? basophils
- ? Neutrophils
vasodilation - ?
- lysosomal
edema - enzymes?damage the tissue
11Immune 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.
12(No Transcript)
13IMMUNE 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)
14Bumpy appearance of immune complexes deposited
in the glomerulus in SLE
15Renal 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
16(No Transcript)
17ACUTE 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.
18(No Transcript)
19IgA 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
20(No Transcript)
21Cell-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 cell-mediated) 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.
22Mechanisms of graft rejection
Inflammation
ADCC
lysis
rejection
23Immune 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(idiopathi
c membeanous nephropathy)with HLA-
II(DR3?DR2?DQ2?DQ1) Minmal change nephrosis with
HLA-DR7?DR9
24Diagnosis
- 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..
25Urinalysis
- 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.
26Serologic 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..
27Histocompatibility 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 HLA-DR2.
28(No Transcript)
29(No Transcript)
30(No Transcript)
31(No Transcript)
32LUPUS NEPHROPATHY
33(No Transcript)
34(No Transcript)
35(No Transcript)
36(No Transcript)
37Thank you !