Immunologic mechanisms of renal diseases

chen weilin

Institute of Immunology, ZJU

Email：cwl@zju.edu.cn

• 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

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) neutrophil activation

2. target cell dysfunction

Cytotoxic Antibody-mediated Renal Disease

• Prototype: Anti-GBM disease (Goodpasture's disease)抗基膜性肾小球肾炎

• Renal damage is caused by linear deposition of antibody specific for type IV collagen α3 chain 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.

肺出血 &

肾小球肾炎

Goodpasture syndrome:

肾小球基底膜抗原 连续线形荧光

glomerular inflammation and severe

damage

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.

Epithelial cell injury.

The postulated sequence is a consequence of antibodies against epithelial cell

antigens, toxins, cytokines, or other factors causing injury with foot process

effacement and sometimes detachment of epithelial cells and protein leakage

through defective GBM and filtration slits.

Cells involved glomerular injury • 1 Neutrophils and monocytes infiltrate the glomerulus in

certain types of glomerulonephritis, largely owing to activation

of complement, resulting in generation of chemotactic agents

(mainly C5a), but also by Fc-mediated adherence and

activation. Neutrophils release proteases, which cause GBM

degradation; oxygen-derived free radicals, which cause cell

damage; and arachidonic acid metabolites, which contribute to

the reductions in glomerular filtration rate (GFR).

• 2 Macrophages, T lymphocytes, and natural killer (NK)

cells, which infiltrate the glomerulus in antibody- and cell-

mediated reactions, when activated release a vast number of

biologically active molecules.

Cells of glomerular injury

• 3 Platelets aggregate in the glomerulus during immune-

mediated injury. Their release of eicosanoids and growth

factors may contribute to the manifestations of

glomerulonephritis. Antiplatelet agents have beneficial effects

in both human and experimental glomerulonephritis.

• 4 Resident glomerular cells, particularly mesangial cells,

can be stimulated to produce several inflammatory mediators,

including reactive oxygen species, cytokines, chemokines,

growth factors, eicosanoids， nitric oxide, and endothelin. In

the absence of leukocytic infiltration, they may initiate

inflammatory responses in the glomerulus.

Soluble mediators

• Complement components induce leukocyte influx and lead to formation of MAC.

• Pro-inflammatory cytokines, IL-1 and TNF, induce leukocyte adhesion.

• Chemokines such as MCP-1 and RANTES promote monocyte and lymphocyte influx. Growth factors, PDGFare involved in mesangial cell proliferation. TGF-β and fibroblast growth factor appear to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury.

• The coagulation system is also a mediator of glomerular damage. Fibrin is frequently present in the glomeruli in glomerulonephritis, and fibrin may leak into Bowman space, serving as a stimulus for parietal epithelial cell proliferation (crescent formation).

Mechanisms of chronic tubulointerstitial injury in glomerulonephritis.

Various components of the protein-rich filtrate and cytokines derived from leukocytes cause

tubular cell activation and secretion of cytokines, growth factors, and other mediators.

These, together with products of macrophages, incite interstitial inflammation and fibrosis.

ET-1, endothelin-1, PAI-1, plasminogen activator inhibitor-1; TIMP-1, tissue inhibitor of

metalloproteinases.

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 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.

Inflammation

lysis

ADCC

lysis

IL2,

IFN(

TNF, NO2

IL2, IL4, IL5

IL2, TNF, IFN(

rejection

Mechanisms of graft 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.

• Immunofluorescence 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.

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 HLA-

DR2.