Top Basic Science Advances for Rheumatology in 2012


Beyond the discovery of new disease genes, revelations about how how our microbes influence our immunity and about many new subtypes of T cells--a mixture of commitment and plascticity.

The basic science underpinning rheumatology advanced rapidly in 2012 on five fronts, as identified by Daniel Kastner MD PhD, scientific director of the National Human Genome Research Institute:

•   Genome-wide association studies (GWAS) have revealed that "junk DNA" is actually the origin of regulatory genes associated with many autoimmune diseases

•   Next-generation DNA sequencing is identifying rare genetic variants in individual patients with rare forms of autoimmune disorders that may begin to account for genetic risks that are not explained by GWAS.

•   New subsets of T cells have been identified that show variation not only by function but by location. Their function may also be influenced by their immediate environment (for instance, whether proinflammatory or anti-inflammatory).

•   Innate immunity may seem evolutionarily simple, but is in fact is proving extraordinarily complex.

•   The microbiome, the communitiy of commensal microorganisms with which we coexist, turns out to have a tremendous influence on the development and homeostasis of our immune response.

The following are Dr. Kastner's choices for the most important scientific reports of 2012 relevant to the field of rheumatology:


Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis.N Engl J Med. (2012) 367:214-23

GWAS data from UK patients validated in similar Northern European cases and controls showed that ANCA-associated vasculitis is genetically distinct from granulomatosis with polyangiitis and microscopic polyangiitis and that forms of ANCA-associated vasculitis involving one of two different enzymes (proteinase 3 or myeloperoxidase) are distinct autoimmune syndromes

Maurano MT, Humbert R, Rynes E et al. Systematic localization of common disease-associated variation in regulatory DNAScience (2012) 337:1190-1195

The genetic variants associated with many common diseases are concentrated in regions of regulatory DNA hypersensitive to transcription, and these variants "systematically" perturb the process of transcribing genes and alter the structure of the chromatin surrounding DNA. Using this knowledge, the researchers have been able to identify new pathogenic cell types for Crohn's disease and multiple sclerosis without prior knowledge of the underlying mechanisms.

Keinan A and AG Clark. Recent explosive human population growth has resulted in an excess of rare genetic variantsScience. (2012) 336:740-743

Explosive human population growth over the past 400 generations has increased the load of rare genetic variants--essentially errors introduced into the human genome. One price we pay for our rapid proliferation as a species is the current genetic burden of rare and common diseases.

Raychaudhuri S, Sandor C, Stahl EA et alFive amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritisNat Genet. (2012) 44:291-296

The well-known linkage between the major histocompatibility locus and rheumatoid arthritis (RA) is now understood, after exhaustive analysis of DNA from nearly 20,000 RA patients and healthy controls.  It comes down to merely 5 amino acid positions, which appear to affect the presentation of antigenic peptides to T-cells.

Large-scale sequencing projects reported in 2012 have identified numerous new disease loci for autoimmune and rheumatologic conditions, including:

-- a dominantly inherited inflammatory disorder characterized byskin lesions, arthralgia, and mild autoimmunity similar to cold urticaria, but not triggered by cold temperatures (Zhou Q, Lee GS, Brady J et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency  Am J Hum Genet. (2012) 91:713-720)

-- cold urticaria itself, associated with a different variant within the same gene (Ombrello M.J., Remmers E.F., Sun G., et al. Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 DeletionsN Engl J Med 2012; 366:330-338)

-- a rare primary hypertrophic osteoarthropathy, here shown to be caused by inactivation of prostaglandin E2 (PGE2) transport (Zhang Z, Xia W, He J et alExome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathyAm J Hum Genet. (2012) 90:125-132)

-- psoriasis, traced to a gene that activates nuclear factor kappa B (NF-kB), presumably triggered by an epidermal injury to set into motion a "vicious cycle of epidermal inflammation and regeneration" (Jordan CT, Cao L, Roberson ED et al. PSORS2 is due to mutations in CARD14Am J Hum Genet. (2012) 90:784-795)

-- osteogenesis imperfecta, traced to a gene that is expressed only in bone (Cho TJ, Lee KE, Lee SK et alA single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type VAm J Hum Genet. (2012) 91:343-348)

--one of the heterogeneous congenital myopathy syndromes, the genetic association confirmed in a zebrafish model (Majczenko K, Davidson AE, Camelo-Piragua S, et alDominant mutation of CCDC78 in a unique congenital myopathy with prominent internal nuclei and atypical coresAm J Hum Genet. (2012) 91:365-371)

-- Marfan syndrome. A mutation in the gene for transforming growth factor beta 2 (TGFB2) indirectly leads to an increase in production of that growth factor in aorta, accounting for the cardiac comorbidity (Boileau C, Guo DC, Hanna N, et alTGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndromeNat Genet. (2012) 44:9169-21)

-- Waldenstrom's macroglobulinemia. A mosaicism: a somatic mutation involving NF-κB signaling affects tumor cells but not normal cells (Treon SP, Xu L, Yang G et alMYD88 L265P Somatic Mutation in Waldenstrm's MacroglobulinemiaN Engl J Med (2012) 367:826-833)

-- a malignancy often associated with Felty syndrome. STAT3 mutations were associated with coexisting neutropenia and rheumatoid arthritis (Koskela HL, Eldfors S, Ellonen P, et alSomatic STAT3 mutations in large granular lymphocytic leukemiaN Engl J Med. (2012) 366:1905-1913).


Kuchroo VK, Ohashi PS, Sartor RB, and CG Vinuesa. Dysregulation of immune homeostasis in autoimmune diseases.
Nat Med. (2012) 18:42-47

This review, available in full text for free, describes in fascinating detail the many ways in which immune responses can go awry to set off an autoimmune disorder. For instance:

•  major histocompatibility molecules maybe unable to achieve the deletion of T cells that react against self, allowing them to "seed the peripheral immune compartment" and be activated by interferons or pathogens.

•  the presence or absence of an important commensal microbe can upset the balance between effector and regulatory T cells, initiating a chronic inflammatory response.

The review also describes newfound functionally specialized subsets of  regulatory T cells that act to suppress specific subsets of effector T cells. But the environment matters critically: Some effector T cells may evolve within their immediate environment (a joint, say) to have different functional characteristics than their counterparts in the lymph nodes. Regulatory T cells may not be able to respond as efficiently in an inflammatory environment as in a non-inflammatory setting.

Daunting as this all may sound, it has important implications for therapy, the authors conclude. Inhibiting tissue inflammation while boosting regulatory T cell function, they write, "may induce long-term and lasting resolution of immune-mediated diseases in a tissue-specific and effector-subset–specific manner."

Bilate AM and JJ Lafaille. Induced CD4+Foxp3+ regulatory T cells in immune toleranceAnnu Rev Immunol. (2012):30:733-758

This review describes differences between natural regulatory T cells, which arise in the thymus, and induced regulatory T cells, which develop outside the thymus triggered by antigen presentation both under noninflammatory conditions and in the setting of chronic inflammation and infections.

Samstein RM, Arvey A, Josefowicz SZ et al  Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specificationCell (2012) 151:153-166

This study describes the "opportunistic" manner in which the molecule Foxp3 defines regulatory T cell functionality by relying on preformed structures within chromatin.

Josefowicz SZ, Niec RE, Kim HY et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammationNature. (2012) 482:395-399

Studies in mice deficient in T regulatory cells suggest that differentiation of T regulatory cells outside the thymus impacts commensal microbiota and specifically restrains allergic-type inflammation at mucosal surfaces.

Kong N, Lan Q, Chen M et alAntigen-specific transforming growth factor β-induced Treg cells, but not natural Treg cells, ameliorate autoimmune arthritis in mice by shifting the Th17/Treg cell balance from Th17 predominance to Treg cell predominanceArthritis Rheum. (2012) 64:2548-58

In a collagen-induced mouse model, specifically triggered T regulatory cells alleviate established autoimmune arthritis while "natural" (thymus-derived) T cells do not, with obvious possible implications for humans with autoimmune disease. The results are discussed in an editorial. (Fox DA. Treg cells to the rescue. Arthritis Rheum. (2012) 64:2426-2428)

Zhu S, Pan W, Song X et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-αNat Med. (2012) 18:1077-1086

From inflammatory lesions of humans with lupus or RA and the corresponding mouse models, researchers learn how IL-17 contributes to autoimmune pathogenesis, by suppressing expression of a microRNA and promoting that of proinflammatory cytokines.

Sherlock JP, Joyce-Shaikh B, Turner SP, et al.IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cellsNat Med. (2012) 18:1069-1076

A mouse model of spondylopathies reveals why dysregulation of IL-23 causes inflammation: It acts on a previously unidentified set of T cells resident in the entheses to activate bone remodeling.



Franchi L, Munoz-Planillo R and G Nunez. Sensing and reacting to microbes through the inflammasomesNat Immunol (2012) 13:325-332

This review describes the multiprotein oligomers known as inflammasomes, which induce responses to microbial invasion. Understanding what happens when they malfunction should provide insights into development of inflammatory disorders.

Shimada K, Crother TR, Karlin J et al. Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during ApoptosisImmunity (2012) 36:404-414

What sets an inflammasome into action? Danger signals (oxidized mitochondrial DNA) released by damaged organelles. The finding is discussed in Fabio Martinon, Dangerous Liaisons: Mitochondrial DNA Meets the NLRP3 Inflammasome. Immunity (2012) 36:313-315

Qu Y, Misaghi Shahram, Izrael-Tomasevic A et al, Phosphorylation of NLRC4 is critical for inflammasome activation  Nature  (2012) 490:539-542

In addition, a receptor expressed in innate immune cells can sense the presence of bacteria and respond by triggering the creation of the inflammasone complex.

Flgel U, Burghoff S, van Lent PL et al, Selective Activation of Adenosine A2A Receptors on Immune Cells by a CD73-Dependent Prodrug Suppresses Joint Inflammation in Experimental Rheumatoid Arthritis. Sci Transl Med (2012) 146:146ra108 

CD73, an enzyme on the plasma membrane that checks whether the environment is proinflammatory or anti-inflammatory by sensing the presence of adenosine, activates a selective prodrug in a study involving mice with collagen-induced arthritis, potently reducing inflammation. The study suggests a new strategy for targeted immunotherapy. An editorial expands on the report (Szabo C and P Pacher. The Outsiders: Emerging Roles of Ectonucleotidases in Inflammation. Sci Transl Med (2012) 4:146ps14)


Obermann HL and S Bauer. Toll-like receptor 9, what o'clock is it?Immunity (2012) 36:159-161

In a mouse study, the effectiveness of vaccination and the severity of sepsis, both governed by toll-like receptor 9, varied depending on the time of day of the triggering event, with "important implications for immunoprophylaxis and immunotherapy." See also the editorial by Silver AC, Arjona A, Walker WE and E Fikrig. The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity (2012)  36(2): 251–261   


Hooper LV, Littman DR, and AJ Macpherson. Interactions Between the Microbiota and the Immune SystemScience (2012) 336:1268-1273

These authors review advances in  understanding of the interactions between resident microbes and the immune system, and the implications for human health--many of them made apparent only by DNA sequencing, which detects microbes that can't be cultured.

Chung H, Pamp SJ, Hill JA et al.Gut immune maturation depends on colonization with a host-specific microbiota. Cell (2012) 149:1578-1593

Germ-free mice instilled at birth with human gut microbes developed far worse protection against Salmonella than those set out on life with a gut microbiome native to their species, although adding mouse-derived microbes afterwards boosted their T cell function some. A host-specific microbiome appears crucial for a healthy immune system.

Sonnenberg GF, Monticelli LA, Alenghat T et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. (2012)336:1321-1325.

IL-22 produced by innate lymphoid cells keeps commensal bacteria from leaving the gut. Depleting IL-22-producing cells from the intestines of mice causes systemic inflammation and peripheral spread of commensal bacteria, which these researchers could prevent by administering IL-22 itself. The escaping bacteria were identified as Alcaligenes, which have been associated with specific systemic immune responses in patients with Crohn's disease.


This article is adapted from a presentation at the 2012 annual meeting of the American College of Rheumatology.


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