Intratumoral immunoglobulin isotypes predict survival in ...
GRAND ROUNDS 6.18...isotypes, IgG1 and IgG3 are capable of binding C1q and leading to C4 activation...
Transcript of GRAND ROUNDS 6.18...isotypes, IgG1 and IgG3 are capable of binding C1q and leading to C4 activation...
GRAND ROUNDS
6.18.13
CASE 55 y.o Hispanic Male with history of HTN, GERD, NASH, RA (+ CCP, + RF), urticarial rash presented to the hospital with fevers, rash and headaches 3 days PTA Pruritic rash started on his forearms and spread to involve the torso sparing face, LE, genitalia ROS: DOE and chronic productive cough Denies mouth ulcers, photosenstivity, dry eyes, dry mouth, joint pains, abdominal pain, n/v, urinary complaints No sick contacts, no recent travel
PMH RA was diagnosed at age 25 in mexico when he presented with hand, wrist, ankle and feet swelling and stiffness. He was not really treated with medications until he came to US. Seen last in Arthritis clinic in 2007, was on enbrel at that time. Off Enbrel since 2007 without any joint complications. Not on MTX due to work up of NASH Thyroglossal duct cyst? CT neck done to evaluate left neck sided fullness/mass in 12/12 showed lesion adjacent to the left throid cartilage s/p FNA 2/6/13 epitheloid cell proliferation in background of acute inflammation PSHx: Knee replacement Home medications: HCTZ/Losartan 50/12.5 Nexium Family history: No h/o SLE or RA No history of kidney disease Social history: h/o second hand smoke. No alcohol or IVDU. Originally from mexico, moved to US 20 years ago
Physical Exam: O VS: T 103.9 BP 128/70 HR 129 RR 20 SO2
97% O Gen: NAD O HEENT: no oral lesions O Neck: No LAN O Lungs: bibasilar rales O CVS: RRR, normal S1S2 O Abd: soft, nt, nd, bs +ve, hepatomegaly O Ext: no edema O Skin: erythematous, raised non blanching,
plaques (varying sizes) over chest, back, arms, palms
Labs
O LFTs: TP 7.0 albumin 2.3 alk phos 72 AST 65 ALT 40 O Lipid panel: LDL 35 TG 130 Chol 84 HDL 23 O CT head: no acute process O CXR: Mildly increased interstitial lung makings O New ill defined opacity at the LLL which could represent
atelectasis
Hgb 12.9
WBC 7.4
Plt
125
Na K Cl HCO3
BUN Cr Ca
D#1 133 4.1 100 29 22 1.2 8.3
D#4 136 3.7 103 26 10 0.9 73
O Hospital Course: In the Ed patient received IV fluids and was started on Vancomycin, ceftriaxone and azithromycin to empirically treat meningitis. LP was performed which was negative. Admitted to medicine. Cultures remain negative. Abx were discontinued. Patient was evaluated by rheum, derm, ID, pulm.
O UA: large blood, protein >300 mg/dl, packed RBCs. O Previous UA 2006 negative blood, protein 30 O Up/cr 3.8 g/g O C3 42 (L) (131 2006) O C4 6.9 (L) (19 2006) O C1q <3.6 (L) O RF 219 ( 892 2005) O Cryoglobulin Negative O ANA negative (but positive in 2004 and 2006>1:40) O Anti-dsDNA negative O ANCA negative O Hepatitis serologies negative O CCP >250 positive(2012) O Anti-SSA (RO) ab >8.0( positive) O Negative La, negative smith, negative RNP O Cardiolipin Antibody IgG 11.8 (2013) O Cardiolipin Antibody IgM 10.1 (2013)
CT chest: small bilateral pleural effusions with adjacent lower lobe atelectasis; mild centrilobular emphysema; bronchial wall thickening; non specific mediastinal and axillary LAD Neck CT 12/12 3.4x1.7x1.4 cm lesion adjacent to left thyroid cartilage
Imaging O Hands X-ray: Right hand tiny erosions in 2-4
proximal phalanges and new swan neck deformity in digits 2-4 right hand
O Left hand: healed erosion of fifth metacarpal head and tiny healed erosions of second and fourth proximal phalanx
O Renal U/S: right kidney 12.7 cm left kideny 12.9 cm. There is no hydronephrosis or calculus
A 13 mm avascular exophytic isoechoic lesion left midpole possibly a complex cyst
Renal Biopsy O Light microscopy: Glomerular basement membrane appear prominent
with frequent spikes and holes but no splitting. There is mild focal moderate increase in mesangial matrix and cellularity. There is no fibrin, necrosis or endocapillary proliferation. There is about 10% interstitial fibrosis with proportional tubular atrophy
O Immunofluorescence :There is diffuse and global granular capill ary
loop staining for IgG 3+, IgA 2+, IgM trace, C3 2-3+, C1q 2+, kappa 2-3+, lambda 3+
There is granular tubular basement staining for IgG, C3, C1q O EM: GBM abnormally thickened due to deposits. There are frequent
subepithelial and intramembranous immune complex deposits. There are no subendothelial deposits. There is complete visceral epithelial cell foot process effacement with microvillous transformation and cytoplasmic vacuolization. There are scattered TRI. There is mild increase in mesangial matrix and cellularity
O Diagnosis: membranous glomerulopathy, favor secondary
O Derm biopsy: Intersititial lymphohistiocytic infiltrate with eosinophils- findings are c/w interstitial granulomatous dermatitis as may be seen in the setting of Connective tissue disease process
Membranous nephropathy O Membranous nephropathy is the most
common cause of idiopathic nephrotic syndrome in white adults, accounting for approximately 20% of cases
O 80% of all cases are classified as idiopathic O 20% present with associated clinical
conditions including infections, autoimmune diseases and malignancy
… O Heymann et al first described an animal model of
membranous nephritis, Heyman nephritis
O Active model of HN, rats are immunized with an extract of rat kidney (Fx1A) that contains components of the proximal tubule brush border.
O Passive model of HN induced by passive administration into rats of antiserum of sheep or rabbits that were immunized with an extract of rat kidney
O The primary antigenic target in AHN is megalin, which is
shared by podocytes and proximal tubular epithelial cells
…
O Debeic and Ronco described alloimmunization in mothers of infants with antenatal MN. Mothers became immunized during pregnancy against neutral endopeptidase expressed on syncytiotrophoblastic cells because they were NEP deficient.
J Am Soc Nephrol 16:1205-1213, 2005
… O 50 years later Beck et al reported that majority of IMN
patients (70%) have circulating antibody against PLA2R, a cell surface transmembrane receptor expressed on the surface of podocytes.
O And these subepithelium like deposits are formed from in
situ binding of circulating anti PLA2R autoantibodies to the PLA2R antigen
O The precise biological function of PLA2R in the kidney
and the effect of anti-PLA2R on podocytes are still unknown
O However, autoantibodies to PLA2R are both sensitive and
specific for the disease.
NEJM 2009
Lupus Membranous Nephropathy
O Class V lupus nephritis occurs in one fifth of biopsy proven cases of SLE
O Up to 50% of patients with SLE will have clinically
evident kidney disease at presentation, during follow up, renal involvement will occur in >60% of patients
O When a full house IF pattern is present, a diagnosis
of lupus nephritis should be suspected and the patient must be evaluated for clinical and immunological evidence of SLE
Classification Criteria for the Diagnosis of Systemic Lupus Erythematosus (SLE) O Malar rash: Fixed erythema, flat or raised, over the malar eminences O Discoid rash: Erythematous circular raised patches with adherent keratotic
scaling and follicular plugging; atrophic scarring may occur O Photosensitivity: Exposure to ultraviolet light causes rash O Oral ulcers: Includes oral and nasopharyngeal ulcers, observed by physician O Arthritis: Nonerosive arthritis of two or more peripheral joints, with tenderness,
swelling, or effusion O Serositis: Pleuritis or pericarditis documented by ECG or rub or evidence of
effusion O Renal disorder: Proteinuria >0.5 g/d or 3+, or cellular casts O Neurologic disorder: Seizures or psychosis without other causes O Hematologic disorder: Hemolytic anemia or leukopenia (<4000/L) or
lymphopenia (<1500/L) or thrombocytopenia (<100,000/L) in the absence of offending drugs
O Immunologic disorder: Anti-dsDNA, anti-Sm, and/or anti-phospholipid O Antinuclear antibodies: An abnormal titer of ANA by immunofluorescence or an
equivalent assay at any point in time in the absence of drugs known to induce ANAs
O Any combination of 4 or more of 11 criteria, well-documented at any time during a patient's history, makes it likely that the patient has SLE (specificity and sensitivity are 95% and 75%, respectively).
… O Gianviti reviewed children with full house nephropathy.
3 patients who presented with a glomerulopathy suggestive of lupus nephritis in the absence of other clinical and biological evidence of SLE.
O Renal biopsies showed a “full house” IF pattern and 2 patients also had TRI’s by EM.
O All these patients develop ANA and anti-dsDNA 3,5 and 10 years after their original presentation
O 14 additional patient’s who presented with a full house IF golmerulonephritis in the absence of other features of SLE were reviewed. After a mean follow up of 5.8 years, these patients did not develop serological or clinical evidence of SLE
Pediatr Nephrol 1999:13:683-7
… O Adu et al in 1983 reported 17 patients who
initially presented with idiopathic glomerulonephritis with renal histology suggestive of lupus but absence of clinical and serological evidence. Over a period of one to 14 years, 6 patients developed extrarenal features suggestive of SLE, 9 positive ANA and 12 Anti- dsDNA
Q J Medm 1983
Contrasting Roles of Complement activation and its regulation in membranous nephropathy
O Complement system is involved in defense against microorganisms, the processing of immune complexes and apoptotic debris, and the development of an appropriate immune response.
O Under normal circumstances, complement activation occurs on pathogens and unwanted host material but not on normal host cells
J Am Soc Nephrol 16:1214-1222,2005
J Am Soc Nephrol 16:1214-1222, 2005
Complement Activation in Human and Experimental MN O Experimental data from the Heymann nephritis rat model have shown
that IgG antibodies in subepithelial immune deposits initiate complement activation and C5b-9 mediated damage of the overlying podocyte
O Although most of the pathogenecity of IgG is the result of (gamma) heavy chain constant domains (which form Fc)interacting with the C1q complement proteins and FcYR on inflammatory cells, other effects can be the direct consequence of IgG binding to particular antigens or even its share bulk
O Salant et al showed that depletion of serum complement with cobra venom factor immediately before induction of PHN prevents the foot process effacement and proteinuria completely without affecting the quantity of subepithelial immune complexes
(J. Clin Invest 1980) O Similarly Baker et al showed that C6 depleted rats did not develop
proteinuria in PHN. (AJP 1989)
… O Cybulsky et al showed using an isolated
perfused kidney model of PHN that C8 was required in the plasma perfusate for podocyte injury and proteinuria to occur (J Clin Invest 1986)
O Consistent with complement activation
occuring in human and experimental MN is finding of C3 and C5b-9 in sub epithelial deposits and in the urine
J Am Soc Nephrol 16:1214-1222, 2005
Role of CRP and the alternative pathway in human and Experimental MN
O Although IgG can activate the classical pathway but of the human IgG
isotypes, IgG1 and IgG3 are capable of binding C1q and leading to C4 activation
O Most cases of human idiopathic membranous nephropathy have a
predominance of IgG4 with less IgG3 and no IgG1 in subepithelial deposits. In addition there is little to no demonstrable C1q and C4 in these deposits, consistent with lack of classical pathway activating capacity of IgG4
O Alternative pathway activation and C5b-9 generation on the podocyte in MN
could occur because of absent, dysfunctional or inhibited CRP
O DAF and CD 59 are linked to the rat and human podocyte membrane via a GPI anchor. As its CRP, human podocytes use CR1, whereas rat podocytes have Crry(CR1-realted gene/protein y). Human podocytes use DAF and CR1 to limit C3 and C5 activation
J Am Soc Nephrol 16:1214-1222, 2005
… O Related to this are experimental data in HN showing the presence of antibodies
that bind and inhibit CRP O Crude renal extract preparation(Fx1A) that is used to induce AHN in rats contain
Crry and CD 59 and that within antiserum (generated in sheep as used in PHN), there are antibodies to both crry and CD 59 that can neutralize their complement regulatory activity in podocytes in vitro
O Schiller et al showed , rats that were immunized with renal extract (Fx1A) lacking crry generated autoantibodies that accumulated in sub epithelial deposits but there was no evidence for complement activation in glomeruli and abnormal proteinuria did not result. Disease could be reconstituted through the inclusion of recombinant Crry in the immunogen or by the passive transfer of anti-Crry antibodies. Thus the generation of autoantibodies to functional podocyte CRP could render these cells susceptible to complement activation and C5b-9 formation
O Although such antibodies have not been documented in human MN O A decrease in the CR1 quantity on the podocyte has been observed, in particular
in lupus nephritis
J Am Soc Nephrol 16:1214-1222, 2005
Signaling pathways activated by assembly of C5b-9
AJP –Renal physiology 2005
Randomized, Controlled Trial of Prednisone, Cyclophosphamide, and Cyclosporine in Lupus Membranous Nephropathy Howard A Austin, Garbor G. Illei, Michelle J Braun and James E.Below
O 42 patients patients participated in randomized control trial to compare adjunctive immunosuppressive drugs with prednisone alone
O Adjunctive treatments included either cyclosporine(CsA) for 11 mo or alternate
month intravenous cyclophosphamide(IVCY) for 6 doses O Primary outcome- time to remission of proteinuria during the 12-mo protocol was
assessed by univariate survival analysis O At 1 year, the cumulative probability of remission was 27% with prednisone,
60% with IVCY and 83% with CsA O Although both IVCY and CsA were more effective then prednisone in inducing
remissions of proteinuria, relapse of nephrotic syndrome occurred significantly more often in after completion of cyclosporine
O Proteinuria <5g/d was associated with increased probability of remission
JASN 2008
… O Two thirds of those who achieved remission in
each adjunctive treatment group 6/9 with IVCY and 6/10 with CsA and 2/4 in control group experienced a complete remission.
… Risk for relapse O Patient who had a remission of proteinuria
were subsequently followed on low dosage alternate day prednisone (10 mg/m2)
O During extended follow up, the incidence of relapse per 100 patient-months was 2 with CsA and 0.2 IVCY
O Pooled analysis of two large randomized controlled multicenter trials of patients who had pure class V disease
O These patients received MMF or IV cyclophosphamide induction therapy for 24 weeks with percentage change in proteinuria and serum creatinine as end points
Kidney International 2010 77,152-160
Kidney International 2010 77,152-160
Kidney International 2010 77,152-160