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Immunologic mechanisms of renal diseases

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Immunologic mechanisms of renal diseases Chen weilin PH.D Institute of Immunology, ZJU Email cwl_at_zju.edu.cn * The histopathology is characterized by necrotizing ... – PowerPoint PPT presentation

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Title: 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 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)

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.

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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

11
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.

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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)

14
Bumpy appearance of immune complexes deposited
in the glomerulus in SLE
15
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

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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.

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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

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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.

22
Mechanisms of graft rejection
Inflammation
ADCC
lysis
rejection
23
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
24
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..

25
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.

26
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..

27
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.

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LUPUS NEPHROPATHY
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Thank you !
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