1. Immunologic mechanisms of renal diseases
Chen weilin，PH.D
Institute of Immunology, ZJU

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 WITH IMMUNOLOGICALLY 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.
The histopathology is characterized by necrotizing destruction of the glomerular architecture and by fibrin deposition in fibroepithelial crescents. 肺出血-肾炎综合征又称抗基膜性肾小球肾炎、Goodpasture综合征或Goodpasture病。它是由抗基膜抗体导致的肾小球和肺泡壁基膜的严重损伤，临床表现为肺出血、急进性肾小球肾炎和血清抗肾小球基膜(GBM)抗体阳性三联征。多数患者病情进展迅速，预后凶险。Goodpasture于1919年首先作了在一次暴发性流感中的肾小球损伤合并肺出血的报道。抗Ⅳ型胶原α3链抗体(抗GBM抗体)阳性

9. 抗中性粒细胞胞浆抗体（ANCA）也可引起细胞毒抗体介导的免疫性肾脏病。在Wegener肾小球肾炎和其他血管炎性肾脏病中起着作用。虽然免疫光检查中无免疫成分的沉积而表现为寡免疫性，最好是将ANCA相关的肾脏病归入免疫介导性肾脏病的范畴内，因为ANCA起了成因作用。尽管存在着不同类型的ANCA，每一类均辨认一个特殊的中性粒细胞胞浆成分（如髓过氧化物酶，溶酶酶，弹性蛋白酶，蛋白酶3，乳铁蛋白，组织蛋白酶B，D，G），但大多数含ANCA的血浆只特异性针对一种抗原。实际上，所有C-ANCA只特异地针对蛋白酶3，而P-ANCA针对髓过氧化物酶。Wegener肉芽肿是ANCA介导的肾脏疾病的原型，几乎所有该病病例与ANCA相关。
特发性坏死性新月体肾炎

10. 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

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.
The underlying mechanisms, in which parenteral administration of foreign protein elicits production of antibody that combines with the antigen as immune complexes in the kidney after the antigen has been planted or in the circulation to be subsequently deposited

13. 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)
The total incidence of renal involvement among patients with SLE probably exceeds 90 percent since renal biopsy in patients without any clinical evidence of renal disease often reveals a focal or diffuse proliferative glomerulonephritis
There are a number of different types of renal disease in SLE, with immune complex-mediated glomerular diseases being most common

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

17. 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.
On electron microscopy, these deposits are semilunar or hump-shaped and located in the subepithelial area. The presence of these deposits initiates a C-mediated inflammatory reaction that leads to glomerular damage. Although the immune complex is presumed to contain an antigen related to streptococcal organisms, no such antigen has been found.

19. 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

21. 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.
HLAs on cells of the transplant are processed by monocytes and macrophages, which release interleukin-1 and activate helper T cells.
Activated helper T cells stimulate other T cells in the presence of interleukin-2, transforming them to cytotoxic T cells that can attack foreign antigens of the graft, resulting in cell-mediated immune inflammation.

22. Mechanisms of graft rejection
TNF, NO2
IL2, TNF, IFN(
Inflammation
IL2, IL4, IL5
lysis
IL2, IFN(
Generation of cytotoxic T lymphocytes
Another consequence of the MHC antigen and T cell interaction is the induction of cytotoxic T‑lymphocytes. When T‑lymphocytes are cultured in the presence of allogeneic lymphocytes, in addition to undergoing mitosis (MLR), they also become cytotoxic to cells of the type that stimulated MLR (Figure 3). Thus, T‑lymphocytes of 'x' haplotype cultured over 5‑7 days with B lymphocytes of 'y' haplotype will undergo mitosis and the surviving T‑lymphocytes become cytotoxic to cells of the 'y' haplotype. The induction of mitosis in MLR requires disparity of only class II antigens whereas the induction of cytotoxic T‑lymphocytes (CTL) requires disparity of both class I and class II antigens. However, once cytotoxic cells have been induced, the effector cytotoxic cells recognize only class I antigens to cause cytotoxicity.
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（idiopathic 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.

28. The commonest cause of the nephrotic syndrome in children
The commonest cause of the nephrotic syndrome in children. Electron microscopy reveals diffuse loss of foot processes of epithelial cells. (Really the epithelial cells are swollen and this flattens the foot processes. This happens in many other glomerular diseases.)
There is no obvious evidence of immunologic disturbance, and the glomeruli appear normal by light microscopy.
Proteinuria is heavy but selective (unlike most glomerular diseases), and renal function remains good.
The long-term prognosis is excellent, often with dramatic response to corticosteroid therapy. (For the idiopathic lesion in adults, it is not so good, and 5% of children have a chronic relapsing-remitting course.
The molecular pathology involves an unexplained loss of polyanions from the GBM, making it more permeable to albumin; nobody knows exactly how this causes foot process fusion, but it probably does

30. This is an anatomist's diagnosis which covers a variety of relatively minor illnesses, including mild systemic lupus, resolving post-streptococcal glomerulonephritis, * rheumatoid arthritis, * maybe hepatitis B, etc
For most of these patients, the prognosis is good.
Patients with IgA deposition have IgA nephropathy and have microhematuria and mild proteinuria. Patients with C3-only have "C3-nephropathy" and have the same clinical picture.
*Patients with IgM deposition have "IgM nephropathy" and usually have more proteinuria and good response to treatment (try cyclophosphamide). Patients with C1q-only have "C1q-nephropathy" and have the same clinical picture.

31. Lab findings that support the diagnosis include increasing anti-streptolysin O ("ASO") titers and decreased C3 levels in the serum.
Other causes of diffuse proliferative GN include infections -- staphylococcal infections, infected AV shunts, overwhelming sepsis and a number of viral illnesses -- and also severe systemic lupus (often causes necrosis
*Post-viral glomerulonephritis is a trivial disease with microhematuria and depressed complement levels but no other symptoms or signs. Diffuse proliferative GN with IgE can be part of the hypereosinophilic syndrome (i.e., T-cell proliferation producing interleukin 5).

32. LUPUS NEPHROPATHY

33. This reaction pattern is the commonest cause of nephrotic syndrome in adults (* most common in middle-aged men.
Some patients have only mild proteinuria, and many of these recover completely. Around half of adults go on to chronic renal failure after years of heavy, nonselective proteinuria.
Electron microscopy shows uniform, evenly-spaced subepithelial immune-complex deposits. Immunofluorescence shows a finely granular pattern of IgG (* almost all IgG4:), C3, sometimes more.
*Though polys are not involved, complement-fixation is required for damage in this disease. The deposits form in-situ at sites where there's normally a sticky antigen .
These deposits soon become incorporated into the GBM, making it look thicker on light microscopy (hence the name "membranous". Except in the earliest stage, spikes of GBM between the immune complexes are easy to see using PAS or silver stains.)

34. An anatomist's diagnosis, not a specific disease
An anatomist's diagnosis, not a specific disease. A pattern of immune-complex disease in which mesangial cells proliferate and send cell processes between basement membrane and endothelial cells.
This gives the glomerular capillary walls a "double contour" or "tram track" appearance
The mechanism of injury is immune complex deposition with activation of the classical complement pathway.
The immune-complex deposits are irregular in size and shape, located subendothelially, subepithelially, and mesangially, often extending from one region to another, contain IgG, C3, C4, C1q, etc
Many cases exhibit "C3 nephritic factor" (an autoantibody which stabilizes alternate-pathway C3 convertase) in the serum. This causes excessive activation of complement, low C3 levels.
Although most cases are idiopathic, identifiable causes include infected shunts, SBE, malaria, schistosomiasis, hepatitis B virus (again, Rx alpha-IF), hepatitis C virus (big review NEJM 328: 465, 1993, alpha-IF helps once again), sickle cell disease, heroin use, leukemia, lymphoma, SLE, cryoglobulinemia, C1-esterase inhibitor deficiency (Am. J. Kid. Dis. 19: 526, 1992).
MCGN I most often affects young people, and presents variable clinical manifestations (nephrotic syndrome, nephritic syndrome, asymptomatic hematuria and proteinuria, sometimes RPGN.)

35. This pattern is most common in young people
This pattern is most common in young people. It begins with asymptomatic hematuria or the nephrotic syndrome.
Dense band-like deposits within the GBM are visible on electron microscopy.
Immunofluorescence shows these contain C3 but no C1q, C4 or Ig. Serum C3 is greatly reduced, while C4 remains normal. (The alternate complement pathway is being activated. C3NeF may be involved. Some patients have inborn deficiencies of complement components.)

36. This syndrome involves rapid, loss of renal function (typically loss of at least 50% of renal reserve over 3 months), usually with the nephritic syndrome.
The morphologic correlate is severe glomerular injury (i.e., many crescents). There are several familiar causes
RPGN I: anti-GBM disease
RPGN II: RPGN superimposed on any immune complex disease
RPGN III: RPGN without significant immune deposits; usually with systemic vasculitis syndromes
Goodpasture's syndrome is anti-GBM disease with RPGN and lung hemorrhages. (The auto-antibody cross-reacts with the pulmonary basement membrane.) It usually occurs in young men. Patients commonly asphyxiate on their own blood after a few months, unless they die of renal failure first

37. Thank you ！