What is the role of

HLA-DRB1*15 in Still's disease

Michael Ombrello

Translational Genetics and Genomics Section NIAMS Intramural Research Program

D ISCLOSURES

• · No conflicts of interest

W HAT ARE H UMAN L EUKOCYTE A NTIGEN (HLA) P ROTEINS ?


W HAT ARE H UMAN L EUKOCYTE A NTIGEN (HLA) P ROTEINS ?

A family of proteins expressed on the surface of antigen presenting cells to display protein fragments (peptides or antigens) in a standardized way that enables T cell surveillance


W HAT IS HLA-DRB1*15?


W HAT IS HLA-DRB1*15?

· A common class II HLA allele group

• · IE. HLA-DRB1*15:01, *15:02, *15:03, etc.

· Common Eurasian ancestral haplotype

• · DR15 ( DRB1*15:01 + DRB5*01:01 )
• · DQ6 ( DQA1*01:02 + DQB1*06:02 )
• · Cw7-B7 (C*07:02 + B* 07:02 )

· Immunologically relevant


• · Strongest genetic risk factor for MS
• · RA, SLE, narcolepsy and Goodpasture disease
• · ABPA, egg allergy, ragweed
• · Altered immunity against EBV

W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND S YSTEMIC JIA?

HLA-DRB1*15 A LLELES A RE N OT A SSOCIATED WITH S JIA



9 independent case-control populations


HLA-DRB1*15 D OES NOT A SSOCIATE WITH S JIA IN I MMUNO C HIP S TUDY



Both of these studies were stringently controlled for ancestry at a genetic level


HLA-DRB1*15 C ARRIAGE V ARIES BY G EOGRAPHY AND A NCESTRY

Distribution of HLA-DRI5 in Europe; the Near East and North Africa

· HLA-DRB1*15 carriage rates

• · Myanmar 41-84%
• · China 23-27%
• · Europe 20-40%
• · South American 0-25%
• · USA
• · Asian 41%
• · African American 23-30%
• · European 29%
• · Hispanic 20%


Wobma 🡪 0.49 in sJIA

Lerman 🡪 0.74 in sJIA



allelefrequencies.net/hla6004a.asp?all_name=DRB1*15 Eupedia.com/genetics/HLA-DR_distribution_maps.shtml

W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND S TILL ' S -L UNG D ISEASE ?

S TILL ' S -L UNG D ISEASE IS A SSOCIATED WITH HLA-DRB1*15 A LLELES

• 1. Still's-LD carriage of HLA-DRB1*15 = 82%
• 2. Still's-LD (n=47) vs. INCHARGE sJIA
• · HLA-DRB1*15 had an OR of 14.1 [6.4, 31]
• 3. Still's-LD (n=47) vs. 'drug tolerant' sJIA (n=31)
• · HLA-DRB1*15 had an OR 57.6 [11.5, 288]

Thank you to Dr. Correia Marques for sharing this informative figure!


W HAT IS THE R ELATIONSHIP BETWEEN HLA-DRB1*15 AND D RUG R EACTIONS ?

D RUG R EACTIONS IN S TILL ' S D ISEASE A SSOCIATE WITH HLA-DRB1*15 A LLELES

• 1. Drug reaction carriage of HLA-DRB1*15 = 82%
• 2. Drug reaction, no LD (n=18) vs. INCHARGE sJIA
• · HLA-DRB1*15 had an OR 11.0 [4, 30.1]
• 3. Still's with drug reaction (n=65) vs. 'drug tolerant' sJIA (n=31)
• · HLA-DRB1*15 had an OR 54.9 [11.6, 261]


Unique combination of immediate and delayed-type reactions

Thank you to Dr. Correia Marques for sharing this informative figure!



HLA-DRB1*15 in drug reaction (surrogate): 78/92 (84.8%)

W HAT C ONNECTS HLA-DRB1*15 WITH D RUG R EACTION /LD?

• · Coexistant LD and drug reaction with shared HLA association suggests shared pathophysiology, but a specific mechanism unclear
• 1. Reaction to the drug (active ingredient)
• 2. Reaction to the drug (not active ingredient)
• 3. Still's disease-specific compensatory shift (biologic effect of drug)
• 4. Related to viral infection, exogenous modifier or new exposure
• 5. Related to another gene co-inherited on DR15 haplotype
• 6. Something beyond the bounds of my imagination

W HAT C ONNECTS HLA-DRB1*15 WITH D RUG R EACTION /LD?

1. Antigen dependent

• · MHC presentation of altered peptide (neoantigen, hapten)
• · Novel antigenic pathogen or exposure

2. Antigen independent

• · Cytokine shifting/skewing
• · Non-antigenic stimulation
• · Effect of linked non-classical HLA gene


Still's disease!

Acknowledgements

Translational Genetics and Genomics Section, NIAMS

Hiroto Nakano, MD PhD

Mariana Correia Marques, MD

Kathleen Baysac, PhD

Anthony Cruz

Brooke Boyd

Mallika Datta

Ann Marie Szymanski, MD

Alana Platukus

Danielle Rubin

Charles Fisher

Alexis Bailey

Emily Shuldiner

Victoria Arthur, PhD

Andrew Patt, PhD

Elizabeth Baskin



Office of the Clincal Director, NIAMS

Michelle Millwood Carol Lake Ly-Lan Bergeron Estefania De Los Santos

Biodata Mining Section, NIAMS

Zuoming Deng, PhD Stephen Brooks, PhD

Inflammatory Disease Section, NHGRI

Amanda Ombrello, MD

Elaine Remmers, PhD

Daniel Kastner, MD PhD

University of Cincinnati/ CCHMC

Grant Schulert, MD PhD Alexei Grom, MD PhD

Stanford University

Elizabeth Mellins, MD PhD

Vivian Saper, MD

Children's Hospital of Philadelphia

Scott Canna, MD

University of California San Francisco

Jill Hollenbach, PhD

We appreciate the selfless contributions of our patients and their families to our studies of sJIA and AOSD.



Boston Children's Hospital

Lauren Henderson, MD

INCHARGE Consortium

Jordi Anton, MD PhD

John Bohnsack, MD

Dirk Föll, MD

Marco Gattorno MD

Alexei Grom, MD

Johannes-Peter Haas MD PhD

Cladio Len MD

Alberto Martini MD

Kirsten Minden, MD

Elizabeth Mellins MD

Sheila Oliviera, MD PhD

Seza Ozen, MD PhD

Sampath Prahalad, MD

Elaine Remmers, PhD

Angela Rosen-Wolff, MD PhD

Alan Rosenberg, MD

Klaus Tenbrock, MD

Susan Thompson, PhD

Wendy Thomson, PhD

Lucy Wedderburn, MD PhD

Patricia Woo, MBBS PhD

Rae Yeung, MD PhD