Basic Concepts of Immunology in Autoimmune Kidney Disease

Basic Concepts of Immunology in Autoimmune Kidney Disease

Ramón G. Bonegio MD, PhDAssociate Chief of Nephrology

Renal Section, Department of MedicineVA-Boston- Healthcare System and

Assistant Professor of MedicineBoston University School of Medicine

Ramon G.B. Bonegio MBBCh, PhD

• University of Witwatersrand School of Health Sciences, South Africa

• Medicine Registrar @Chris Hani Baragwanath and Charlotte MaxekeJohannesburg Academic Hospitals, South Africa

• Nephrology Fellowship @Boston Medical Center

• Assistant Professor of Medicine@ BU– Clinical focus: Glomerular disease– Research focus: Glomerulonephritis and lupus

nephritis

Conflicts of interest

• Dr. Bonegio is or has been the site investigator for clinical trials sponsored by Astra Zeneca, Aurinia pharmaceuticals, Biogen Inc., Genentech and Bristol Myers Squibb

• Dr. Bonegio has received research funding from Pfizer and Merck pharmaceuticals

Introduction

• Introducing the immune system

– Innate immunity

– Adaptive immune cells

• A few new things to be aware of

– Where is the immune system?

– B cell maturation factors

– The plastic T cell subtypes

• A few cases with possible therapeutic implications

• Conclusions

Parts of the immune system

NK cells

Neutrophils

Macrophages

Eosinophils

Basophils

Dendritic

cells

suPAR

ApoL1

Complement

Innate immunity

PRR >>inflammation

B cells

T cells

Antibodies

Adaptive immunity

Antigen-driven >> long-lasting immunity

Cytokines

and

Chemokines

Where is the immune system?

Where is the immune system?

• Gut-associated lymphoid tissue samples antigens from the gut lumen– Critical site of defense

– Critical site tolerance vs effector responses

Ahluwalia et al Scan J. Gastroenterol 2017 and Boston University Histology

Targeted-release formulation (TRF) budesonide ameliorated proteinuria in patients with IgA

nephropathy (NEFIGAN trial)

Fellström et al Lancet 2017

Adaptive immunity: TNF family members regulate maturation and growth of B cells

TACIBAFF-R

BCMA

Adaptive immunity: TNF family members regulate the maturation and growth of B cells

MacKay and Browning Nat Rev Immunol 2002

APRIL and IL-6 synergistically activate IgA producing cells to induce aberrant IgA

glycosylation

Makita et al KI 2020

Adaptive immunity: T cell personalities and immune functions

All have TCR

All are antigen driven

Moderate immuneresponses

Enhance immuneresponses

Q1. A 62 year-old woman presents with ANCA-associated RPGN. Which of the following factors IS LEAST LIKELY to contribute to the severity of her glomerular injury?

1) Neutrophils

2) B cells and plasma cells

3) Complement C5a

4) The complement membrane attack

complex (C5b-9)

5) Autoantibodies targeting proteinase 3

or myeloperoxidase

Thanks Joel Henderson

Complement activation

Modified from Conde et al Front Microbiol 2017

C5aR but not the MAC is requires for crescent formation

Hong Xiao et al. JASN 2014;25:225-231

C5aR-/- C6-/- C5aR-/- with hC5aR

C5aR is requires for neutrophil recruitment to glomeruli and crescent formation

Wild-type

C5aR-/-

Adrian Schreiber et al. JASN 2009;20:289-298

C5aR inhibition in human AAV

David R.W. Jayne et al. JASN 2017;28:2756-2767Phase 3 study currently recruiting – clinical trials.gov NCT02994927

Avacopan + Pred 20

Pred 60

Avacopan only

Q1. A 62 year-old woman presents with ANCA-associated RPGN. Which of the following factors IS LEAST LIKELY contribute to the severity of her glomerular injury?

1) Neutrophils

2) B cells and plasma cells

3) Complement C5a

4) The complement membrane attack

complex (C5b-9)

5) Autoantibodies targeting proteinase 3

or myeloperoxidase

IgG or C1q or C3

Q2. A 24 year-old woman presents with nephrotic range proteinuria and an active urinary sediment. She complains of photosensitivity, hair loss and arthritis

Which of the following are likely targets

that may ameliorate disease

1) The TNF pathways

2) Type 1 interferon pathways

3) C2

4) B cell activation factor (BAFF)

5) CD20+ B cells

Anti-TNF induced lupus

Williams, Galdola and Edwards Rheumatology 2009

C2 and C4 deficiency is strongly associated with SLE risk

Bryans and Wu Curr. All.Asthma Rep 2014

Cytokine blockade

Immune-complex disease

with tissue damage

BLyS

IFNAR

inhibitors

IFNa/b

pDCs

Type 1 interferon as a target in SLE

Emily C. Baechler et al. PNAS 2003;100:2610-2615 Lynda Bennett et al. J Exp Med 2003;197:711-723

Treatment of lupus nephritis: Anifrolumab phase 1-2

Furie et al Arthritis and Rheumatol 2016

Adjusted difference in cumulative proportions of patients with herpes zoster - pooled TULIP-1

and TULIP-2 data.

Raj Tummala et al. Lupus Sci Med 2021;8:e000464

©2021 by Lupus Foundation of America

Targeting B cell activation is effective

Furie et al NEJM 2020

Rituximab in lupus nephritis – LUNAR III

Rovin et al for the LUNAR group Arthritis and Rheumatism 2012

Obinutuzumab - B-cell depletion may work better in SLE patients

Reddy et al, Rheumatology, Volume 56, Issue 7, July 2017

Furie et al 2019 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10).

IgG or C1q or C3

Q2. A 24 year-old woman presents with nephrotic range proteinuria and an active urinary sediment. She complains of photosensitivity, hair loss and arthritis

Which of the following are likely targets

that may ameliorate disease

1) The TNF pathways

2) Type 1 interferon pathways

3) C2

4) B cell activation factor (BAFF)

5) CD20+ B cells Rituximab (case series)

or Obinutuzumab (early studies)

Conclusion• Introducing the immune system

– Innate immunity

– Adaptive immune cells

• A few new things to be aware of– MALT and GALT

– BAFF and APRIL as important B cell maturation regulators

– T cell subtypes

• A few cases with possible therapeutic implications– The role of C5a and the C5aR in AAV

– Targeting specific cell types and cytokine pathways in autoimmune kidney disease

References1. Ahluwalia et al Mucosal Immune System of the Gastrointestinal tract. Scan J. Gastroenterol 2017: 1185-1193

2. MacKay and Browning BAFF: A fundamental survival factor for B cells. Nat Rev Immunol 2002: 465-475

3. Conde et al the Complement System in Flavivirus Infections Front Microbiol 2017: 0213

4. Hong Xiao et al. C5a Receptor (CD88) Blockade Protects against MPO-ANCA. GN: JASN 2014: 225-231

5. Adrian Schreiber et al. C5a Receptor Mediates Neutrophil Activation in ANCA-induced glomerulonephritis. JASN 2009;20:289-298

6. David R.W. Jayne et al. A Ramdomized Trial of C5a Receptor Inhibitor in ANCA-Associated Vasculitis. JASN 2017;28:2756-2767

7. Beck LH Jr et al. M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. N Engl J Med 2009;361:11-21

8. Bruhns et al Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012: 5640-5649

9. Williams, Galdola and Edwards Anti-TNF-indiced lupus. Rheumatology 2009: 716-720

10. Bryans AR and Wu EY Complement Deficiencies in Systemic Lupus Erythematosus. Curr. All. Asthma Rep 2014:448

11. Furie et al Anifrolumab, and Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Lupus Erythematosus. Arthritis and Rheumatol 2016: 376-386

12. Tummala et al Safety profile of anifrolumab in patients with active SLE: and integrated analysis of phase II and III trials

13. Furie et al Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis NEJM 2020: 1117-1128

14. Rovin et al for the LUNAR group Efficacy and Safety of Rituximab in Patients with Active Proliferative Lupus Nephritis: Th Lupus Nephritis Assessment with Rituximab Study. Arthritis and Rheumatism 2012: 1215-1226

15. Reddy et al, Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology m2017: 1227–1237

16. Furie et al 2019 [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10).

17. FellstrÖm et al Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial LANCET 2017; 389: 2117-2127

18. Makita et al TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy Kidney Int2020 92(2): 340-349