Immunologic mechanisms of renal diseases

1
Immunologic mechanisms of renal diseases

• Chen weilin,PH.D
• Institute of Immunology, ZJU
• Emailcwl_at_zju.edu.cn

2
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.

3
ANTIGENS ASSOCIATED WITHIMMUNOLOGICALLY MEDIATED
RENAL DISEASE

4
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.

5
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)

6
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

7
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.

8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
Type 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

12
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.

13
(No Transcript)
14
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)

15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
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

20
Bumpy appearance of immune complexes deposited
in the glomerulus in SLE
21
LUPUS NEPHROPATHY
22
(No Transcript)
23
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.

24
(No Transcript)
25
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

26
(No Transcript)
27
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 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.

28
Mechanisms of graft rejection
Inflammation
ADCC
lysis
rejection
29
Complement activation
Alternative pathway C3 MPGN?--- C3
deposit?antibody ?--- dense
deposit ?--- both above
30
(No Transcript)
31
(No Transcript)
32
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(idiopathi
c membeanous nephropathy)with HLA-
II(DR3?DR2?DQ2?DQ1) Minmal change nephrosis with
HLA-DR7?DR9
33
(No Transcript)
34
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..

35
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.

36
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..

37
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 HLA-DR2.

38
Thank you !