John Routes, MD
Professor, Pediatrics (Allergy, Asthma & Immunology) and Microbiology & Immunology; Chief, Section of Allergy and Clinical Immunology
- Chair, NIH Study Section, Investigations on Primary Immunodeficiency Diseases
- President, Clinical Immunology Society
- Section Head, Asthma, Allergy and Clinical Immunology
Primary Immunodeficiencies (PID)
Interstitial lung disease (ILD) occurs in approximately 10-30% of patients with CVID and is associated with increased morbidity and mortality. The most common form of ILD in CVID has pulmonary granuloma as a component of the histopathological abnormality. Previously, it was thought that this granulomatous ILD represented sarcoidosis in patients with CVID. In 2004 our group demonstrated that the pathology of granulomatous lung disease in CVID was distinct from sarcoidosis and this represented a distinct form of ILD. We found that in addition to granuloma, lymphocytic interstitial pneumonia and follicular bronchiolitis were also characteristic findings and we termed the disorder granulomatous and lymphocytic interstitial lung disease (GLILD). It is now widely recognized that GLILD is a unique form of ILD in CVID. More recently, we published a novel treatment regimen for GLILD that appears to clear the pulmonary infiltrates and improves the pulmonary function in a substantial proportion of patients. My current research seeks to confirm these promising findings and to elucidate the etiology and molecular pathogenesis of GLILD.
I also have a major interest in the use of new technology in screening newborns for PID. In 2007, I raised $500,000 from the Jeffrey Modell Foundation and Children's Wisconsin to start a pilot program using the T cell receptor excision assay to screen all newborns in Wisconsin for Severe Combined Immunodeficiency (SCID). Our group optimized the RT-PCR assay and in 2008 Wisconsin became the first state to screen for SCID. Our group successfully implemented this program and identified babies with SCID using the TREC assay. In 2010, I testified to the SACHDNC regarding our successful use of the TREC assay to identify infants with SCID, which resulted in the recommendation and approval of the addition of SCID to the uniform panel of newborn screening tests recommended by the United States government (PDF). Our group has trained scientists from the several countries and states on properly performing the TREC assay. Currently, over 50% of all infants in the United States are screened at birth for SCID. Numerous countries have implemented or are implementing newborn screening for SCID. I have received international recognition for my leadership role in this major advance in PID and am a lead author on the international consensus document (ICON) on the early diagnosis of congenital immunodeficiencies.
- Routes J, Abinun M, Al-Herz W, Bustamante J, Condino-Neto A, De La Morena MT, Etzioni A, Gambineri E, Haddad E, Kobrynski L et al: ICON: the early diagnosis of congenital immunodeficiencies. Journal of Clinical Immunology 2014, 34(4):398-424.
- Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, Singh S, Shahir KS, Tisol WB, Nugent ML, Routes, J: Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). Journal of Clinical Immunology 2013, 33(1):30-39.
- Routes JM, Grossman WJ, Verbsky J, Laessig RH, Hoffman GL, Brokopp CD, Baker MW: Statewide newborn screening for severe T-cell lymphopenia. JAMA 2009, 302(22):2465-2470.
- Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK,& ;Routes JM: Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 2004, 114(2):415-421.
Small DNA Viruses
My early work sought to define the immunological mechanisms that underlie the rejection of adenovirus (Ad) E1A-expressing tumor cells. Through the use of mouse models, we demonstrated that the rejection of E1A-expressing tumor cells was mediated by NK cells and T cells. In further studies, we demonstrated that the expression of E1A sensitized cells to killing by a variety of immune effector molecules such as nitric oxide, TRAIL and perforin-granzyme. We also demonstrated that the ability of E1A to sensitize cells to NK cells, macrophages and immune effector molecules was not shared with either the E7 oncoprotein from oncogenic HPV. Next, we determined that the expression of E1A in mouse and human cells upregulated NKG2D ligands, thereby sensitizing cells to lysis by NK cells and genetically mapped this activity to the p300 binding site of E1A. This is the first example of a viral oncoprotein upregulating NKG2D ligands. Finally, we demonstrated that the expression of E1A in tumor cells inhibited the production of arginase-1 by tumor associated macrophages in vivo. This activity of E1A likely contributes to the ability of E1A to reduce tumorigenicity. I was first author or senior author on these publications.
- Korrer MJ, Routes JM: Possible role of arginase-1 in concomitant tumor immunity. PLoS One 2014, 9(3):e91370.
- Routes JM, Ryan S, Morris K, Takaki R, Cerwenka A, Lanier LL: Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection. The Journal of Experimental Medicine 2005, 202(11):1477-1482.
- Cook JL, Routes JM: Adenovirus E1A gene-induced tumor cell rejection through cellular sensitization to immune and nonimmune apoptotic injuries. Frontiers in Bioscience; 2005, 10:1396-1414.
- Miura TA, Morris K, Ryan S, Cook JL, Routes JM: Adenovirus E1A, not human papillomavirus E7, sensitizes tumor cells to lysis by macrophages through nitric oxide- and TNF-alpha-dependent mechanisms despite up-regulation of 70-kDa heat shock protein. Journal of Immunology 2003, 170(8):4119-4126.
(Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, Romberg N.) J Exp Med. 2021 Jul 05;218(7) PMID: 33951726 PMCID: PMC8105723 SCOPUS ID: 2-s2.0-85105296806 05/06/2021
(Anderson JT, Bonagura VR, Cowan J, Hsu C, Mustafa SS, Patel NC, Routes JM, Sriaroon P, Vinh DC, Hofmann JH, Praus M, Rojavin MA.) J Clin Immunol. 2021 02;41(2):458-469 PMID: 33409867 PMCID: PMC7858210 SCOPUS ID: 2-s2.0-85099072235 01/08/2021
(Verbsky JW, Hintermeyer MK, Simpson PM, Feng M, Barbeau J, Rao N, Cool CD, Sosa-Lozano LA, Baruah D, Hammelev E, Busalacchi A, Rymaszewski A, Woodliff J, Chen S, Bausch-Jurken M, Routes JM.) J Allergy Clin Immunol. 2021 02;147(2):704-712.e17 PMID: 32745555 SCOPUS ID: 2-s2.0-85089870161 08/04/2020
(Kuehn HS, Niemela JE, Stoddard J, Mannurita SC, Shahin T, Goel S, Hintermeyer M, Heredia RJ, Garofalo M, Lucas L, Singh S, Tondo A, Jacobs Z, Gahl WA, Latour S, Verbsky J, Routes J, Cunningham-Rundles C, Boztug K, Gambineri E, Fleisher TA, Chandrakasan S, Rosenzweig SD.) Blood. 2021 01 21;137(3):349-363 PMID: 32845957 PMCID: PMC7819759 SCOPUS ID: 2-s2.0-85098538966 08/28/2020
(Anderson JT, Bonagura VR, Cowan J, Hsu C, Mustafa SS, Patel NC, Routes JM, Sriaroon P, Vinh DC, Hofmann JH, Praus M, Rojavin MA.) Journal of Clinical Immunology. February 2021;41(2):458-469 SCOPUS ID: 2-s2.0-85099072235 02/01/2021
(Doan J, Rao N, Kurman JS, Routes JM, Benn BS.) Cryobiology. 2020 12;97:231-234 PMID: 32810518 SCOPUS ID: 2-s2.0-85089727939 08/19/2020
(Marsh RA, Leiding JW, Logan BR, Griffith LM, Arnold DE, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu LC, Oshrine BR, Cuvelier GDE, Thakar MS, Chen K, Teira P, Shenoy S, Phelan R, Forbes LR, Martinez C, Chellapandian D, Dávila Saldaña BJ, Shah AJ, Weinacht KG, Joshi A, Boulad F, Quigg TC, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai SY, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM, submitted on behalf of the Primary Immune Deficiency Treatment Consortium.) J Clin Immunol. 2020 Nov;40(8):1211-1213 PMID: 32860171 SCOPUS ID: 2-s2.0-85089900632 08/30/2020
(Momtazmanesh S, Ochs HD, Uddin LQ, Perc M, Routes JM, Vieira DN, Al-Herz W, Baris S, Prando C, Rosivall L, Abdul Latiff AH, Ulrichs T, Roudenok V, Aldave Becerra JC, Salunke DB, Goudouris E, Condino-Neto A, Stashchak A, Kryvenko O, Stashchak M, Bondarenko A, Rezaei N.) Am J Trop Med Hyg. 2020 06;102(6):1181-1183 PMID: 32323644 PMCID: PMC7253116 SCOPUS ID: 2-s2.0-85086052683 04/24/2020
(Tuovinen EA, Grönholm J, Öhman T, Pöysti S, Toivonen R, Kreutzman A, Heiskanen K, Trotta L, Toiviainen-Salo S, Routes JM, Verbsky J, Mustjoki S, Saarela J, Kere J, Varjosalo M, Hänninen A, Seppänen MRJ.) J Clin Immunol. 2020 04;40(3):503-514 PMID: 32072341 PMCID: PMC7142052 SCOPUS ID: 2-s2.0-85079785911 02/20/2020
(Tallar M, Routes J.) Clin Perinatol. 2020 03;47(1):77-86 PMID: 32000930 SCOPUS ID: 2-s2.0-85076832448 02/01/2020
(Vyles D, Chiu A, Routes J, Castells M, Phillips EJ, Visotcky A, Fraser R, Pezzin L, Brousseau DC.) J Allergy Clin Immunol Pract. 2020 03;8(3):1126-1128.e1 PMID: 31586667 PMCID: PMC7332348 SCOPUS ID: 2-s2.0-85073824604 10/07/2019
(Yang C, Siebert JR, Burns R, Gerbec ZJ, Bonacci B, Rymaszewski A, Rau M, Riese MJ, Rao S, Carlson KS, Routes JM, Verbsky JW, Thakar MS, Malarkannan S.) Nat Commun. 2019 09 02;10(1):3931 PMID: 31477722 PMCID: PMC6718415 SCOPUS ID: 2-s2.0-85071610251 09/04/2019