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1. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME

Subjects
Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Published
2017
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2. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T.W., Gerety, S.S., Jones, W.D., van Kogelenberg, M., King, D.A., McRae, J., Morley, K.I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D.M., Bayzetinova, T., Clayton, S., Coomber, E.L., Gribble, S., Jones, P., Krishnappa, N., Mason, L.E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A.R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A.P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S.J., Bunyan, D.J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M.N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D'Alessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, S.L.G., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S.A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D.J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., O'Shea, R., Ogilvie, C., Park, S., Parker, M.J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D.T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweier, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Shanrif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G.J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I.K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N.P., Parker, M., Firth, H.V., FitzPatrick, D.R., Wright, C.F., Barrett, J.C., Hurles, M.E., and The Deciphering Developmental Disorders Study, .

Subjects
Male, Parents, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Transposases, SYNGAP1, medicine.disease_cause, Bioinformatics, DEAD-box RNA Helicases, 0302 clinical medicine, Guanine Nucleotide Exchange Factors, Missense mutation, Exome, Protein Phosphatase 2, Child, Dynamin I, Zebrafish, Exome sequencing, Genes, Dominant, Polycomb Repressive Complex 1, 0303 health sciences, Mutation, Multidisciplinary, Gene Expression Regulation, Developmental, Nuclear Proteins, DNA-Binding Proteins, Child, Preschool, Female, Adolescent, Mutation, Missense, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, 030304 developmental biology, Chromosome Aberrations, Homeodomain Proteins, Genome, Human, Mechanism (biology), Infant, Newborn, Infant, Phosphoproteins, United Kingdom, Human genetics, Repressor Proteins, Human genome, Carrier Proteins, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

3. Landscape of familial isolated and young-onset pituitary adenomas: Prospective diagnosis in AIP mutation carriers

Author

Hernandez-Ramirez, L.C., Gabrovska, P., Denes, J., Stals, K., Trivellin, G., Tilley, D., Ferrau, F., Evanson, J., Ellard, S., Grossman, A.B., Roncaroli, F., Gadelha, M.R., Korbonits, M., Agha, A., Akker, S.A., Aflorei, E.D., Alföldi, S., Arlt, W., Atkinson, B., Aulinas-Masó, A., Aylwin, S.J., Backeljauw, P.F., Badiu, C., Baldeweg, S., Bano, G., Barkan, A., Barwell, J., Bernal-González, C., Besser, G., Bevan, J.S., Blair, J., Bouloux, P., Bradley, L., Buchfelder, M., Cakir, M., Canham N, ., Carroll, P., Chahal, H.S., Cheetham, T., Chentli, F., Clayton, R.N., Cohen, M., Cole, T., Courtney, H., Crowne, E., Cuthbertson, D., Dal J, ., Dalantaeva, N., Daousi, C., Darzy, K., Dattani, M., Davies, J.H., Davis, J., De Castro, M., De Marinis, L., Drake, W., Dutta, P., Dzeranova, L., Edén-Engström, B., Eeles, R., Elfving, M., Elston, M., Emmerson, L., Fersht, N., Fica, S., Fischli, S., Flanagan, D., Fleseriu, M., Freda, P.U., Friedman, T., Frohman, L.A., Gallego, P., Gevers, E., Gláz, E., Goldman, J.A., Goldstone, A.P., Goth, M., Greenhalgh, L., Grieve, J., Guitelman, M., Gürlek, A., Gurnell, M., Horvath, K., Howlett, T.A., Höybye, C., Hunter S, ., Iacovazzo D, ., Igaz, P., Inder, W.J., Iwata, T., Izatt, L., Jagadeesh, S., Kaltsas, G., Kaplan F, ., Karavitaki, N., Kastelan, D., Katz, M., Kearney, T., Khoo, B., Kiraly-Borri, C., Knispelis, R., Kovács, G.L., Kumar, A.V., Laws, E.R., Lechan, R.M., Levy, J., Lewandowski, K., Lo, J., Maartens, N., Matsuno, A., Mcgowan, B., Mcquaid, S.E., Medic-Stojanoska, M., Mercado-Atri, M., Mezősi, E., Miljic, D., Miller, K.K., Modenesi, S., Molitch, M.E., Monson, J., Morris, D.G., Morrison, P.J., Munir, A., Murray, R.D., Musat, M., Musolino, N., Nachtigall, L., Newell-Price, J., Ogilvie, A., Orme, S.M., Paşcanu, I., Patócs, A., Patterson, C., Pearce, S.H., Pecori Giraldi, F., Pfeifer, M., Popovic, V., Poplawski, N., Powell, M., Pullan, P., Quinton, R., Radian, S., Randeva, H., Ribeiro-Oliveira, A., Rodd, C., Ryan, F., Salvatori, R., Schöfl, C., Shears, D., Shotliff, K., Soares, B.S., Spada, A., Sperber, J., Spoudeas, H.A., Stewart, S., Storr, H., Strasburger, C., Street, M.E., Swords, F., Thakker, R.V., Tham, E., Thompson, C., Thorner, M.O., Tóth, M., Trainer, P.J., Tsagarakis, S., Tzanela, M., Vadász, J., Vaks, V., Verkauskiene, R., Wass, J.A., Webb, S.M., Weber, A., Yamada, S., Yarman, S., Yeoh, P., Yoshimoto, K., Zammitt, N.N., and İç hastalıkları

Subjects
Adenoma, Adult, Male, Adolescent, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Genetic Testing, Germ-Line Mutation, Growth Hormone-Secreting Pituitary Adenoma, Humans, Intracellular Signaling Peptides and Proteins, Longitudinal Studies, Middle Aged, Mutation, Pituitary Neoplasms, Prospective Studies, Young Adult, Endocrinology, Diabetes and Metabolism, Biochemistry, Endocrinology, Clinical Biochemistry, Biochemistry (medical), Observational Study, Settore MED/13 - Endocrinologia, Journal Article, 80 and over, Preschool, JCEM Online: Advances in Genetics, Research Support, Non-U.S. Gov't
Abstract

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Published
2015
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4. Pancreatic dysfunction in severe obesity

Author

Drake, A, Greenhalgh, L, Newbury-Ecob, R, Crowne, E, and Shield, J

Subjects
Male, Adolescent, Puberty, Precocious, Body Mass Index, Obesity, Morbid, Pancreatic Function Tests, Diabetes Mellitus, Type 2, Predictive Value of Tests, Risk Factors, Child, Preschool, Hyperinsulinism, General and Specialist Paediatrics, Diabetes Mellitus, Humans, Female, Obesity, Child, Pancreas
Abstract

AIMS—To investigate pancreatic function in children attending an obesity clinic. METHODS—Thirty six children (of which 34 were white) with severe obesity of prepubertal onset (body mass index more than +2 SDS) were reviewed clinically and dysmorphologically, with assessment of pancreatic function. RESULTS—Eight had dysmorphic features and 13 had learning difficulties. Four of 17 prepubertal children had hyperinsulinaemia and seven had hyperproinsulinaemia. All 19 pubertal children had hyperinsulinaemia, 14 had hyperproinsulinaemia, and one had type II diabetes. CONCLUSIONS—Metabolic abnormalities predictive of type II diabetes occur in severely obese white children.

Published
2001

5. Neuroendocrine regulation of immunity: the effects of noradrenaline in Xenopus laevis, the South African clawed toad

Author

Rh, Clothier, Ln, Ruben, Ro, Johnson, Parker K, Sovak M, Greenhalgh L, Eng Eong Ooi, and Balls M

Subjects
Male, Neuroimmunomodulation, Isoproterenol, Antigens, T-Independent, Clonidine, Antigen-Antibody Reactions, Norepinephrine, Xenopus laevis, Catecholamines, Immune System, Peripheral Nervous System, Animals, Female, Mitogens, Oxidopamine, Adrenergic alpha-Agonists, Adrenergic alpha-Antagonists, Spleen
Abstract

A functional association between the peripheral nervous and the immune system in Xenopus laevis, the South African clawed toad, is demonstrated. This association involves the neurotransmitter noradrenaline (NA), produced and released by the sympathetic nerves of the spleen. Chemical sympathectomy prior to immunization reduces splenic NA, and decreases thymus-dependent (TD), but increases thymus-independent (TI), antibody responses. Immune challenge with representatives of the three antigen classes affects splenic NA levels differentially. Thus, the modulatory effect of NA on immunity will depend on the immunogen used. Carrier-priming of helper function in TD responses stimulates a transitory NA release in the spleen, while subsequent immunization activates a more prolonged release. The two types of challenge differ in the antigenic dose given. The effects of NA also depend on the time when it is applied. If used early in the in vivo TD response, antibody production is increased, but if given later, suppressor function is stimulated, thus decreasing antibody production. NA increases both amplifying and suppressing T cell functions in TD responses through stimulation of the alpha 2 adrenoceptor. Alpha 2 adrenoceptor stimulation decreases, and beta adrenoceptor stimulation increases, anti-TNP reactivity. Since an alpha 2 receptor agonist does not affect lectin-stimulated T cell mitogenesis, while a beta receptor agonist depresses it, NA appears to up-regulate T cell functions by affecting their maturation, rather than their clonal expansion.

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