Neurology -- Correspondence for Klünemann et al., 64 (9) 1502-1507

Correspondence published:

Reply to Authors: Hans Klunemann, B. H. Ridha, MRCP, L. Magy, MD, PhD, J. R. Wherrett, MD, PhD, D. M. Hemelsoet, MD, R. W. Keen, PhD, J. L. De Bleecker, MD, PhD, M. N. Rossor, MD, J. Marienhagen, MD, H. E. Klein, MD, L. Peltonen, MD, PhD and J. Paloneva, MD, PhD (27 July 2005)

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2: Marino Muxfeldt Bianchin, Jose Eduardo Lima, Joao Natel, Americo Ceiki Sakamoto (27 July 2005)

Reply to Authors 27 July 2005

Hans Klunemann,
University of Regensburg
Universitaetstr. 84 Regensburg, Germany D-93052,
B. H. Ridha, MRCP, L. Magy, MD, PhD, J. R. Wherrett, MD, PhD, D. M. Hemelsoet, MD, R. W. Keen, PhD, J. L. De Bleecker, MD, PhD, M. N. Rossor, MD, J. Marienhagen, MD, H. E. Klein, MD, L. Peltonen, MD, PhD and J. Paloneva, MD, PhD
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Re: Reply to Authors

hans.kluenemann{at}medbo.de Hans Klunemann, et al.

We agree with Dr. Bianchin and colleagues. An analysis of the immunophenotype and immunological functions of a series of patients suffering from a late stage PLOSL would be valuable.
However, there is no history to suggest recurrent infections, immunodeficiency, autoimmune disease or neoplasia in our small series of six patients with TREM2 mutations. One possible explanation for Bianchin's report is that the mutations may have a protective role as they could theoretically dampen the septic shock mechanism.
Besides TREM-2, TREM-1 is the best-known DAP12-associated receptor that regulates the function of myeloid cells in innate and adaptive responses. Its role in acute inflammatory responses (including sepsis) has been established. TREM-1 amplifies receptor-initiated responses against microbial infection and potentiates the secretion of proinflammatory chemokines and cytokines to infections. It has been shown that blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infection. [1,2] Moreover, it has been shown that a soluble form of TREM-1 can serve as a marker of microbial infection. [3]
However, the role of TREM-2 in sepsis and other infections or inflammatory respsonses is still unclear. Recently, it has been shown that TREM-2 stimulation in microglia induced DAP12 phosphorylation, followed by a cascade of reactions eventually leading to an increased phagocytosis of apoptotic neurons and an decreased microglial proinflammatory response. However, knockdown of TREM-2 in microglia inhibited phagocytosis and increased proinflammatory responses with increased gene transcription of TNF-alpha and NOS-2. [4]
It has been proposed that TREM-2 deficiency results in inflammation which may have a role in the neurodegeneration in PLOSL. The role of DAP12 and TREM-2 in the CNS has been investigated. [5] The authors showed that microglial cell and gligodendrocytes are the major DAP12/TREM-2 producing cells in the CNS, and that they are consequently the predominant cell types involved in PLOSL pathogenesis. This provided evidence for the involvement of the immune system in neuronal degeneration of PLOSL.
The authors report no conflicts of interest.
References
1) Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 2001;410:1103-1107.
2) Colonna M, Facchetti F. TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. J Infect Dis 2003;187 Suppl 2:S397-401.
3) Gibot S, Cravoisy A. Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 as a Marker of Microbial Infection. Clin Med Res. 2004;2:181-187.
4) Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 2005;201:647-657.
5) Kiialainen A, Hovanes K, Paloneva J, Kopra O, Peltonen L. Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS. Neurobiol Dis 2005;18:314-322.

The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2 27 July 2005

Marino Muxfeldt Bianchin,
Ribeirao Preto Medical School
University of Sao Paulo, Brazil,
Jose Eduardo Lima, Joao Natel, Americo Ceiki Sakamoto
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Re: The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2

mmbianchin{at}rnp.fmrp.usp.br Marino Muxfeldt Bianchin, et al.

We read with great interest the article by Kl�nemann et al. [1] DAP12 or TREM2 genes encode different subunits of a cell membrane-associated receptor complex that, when non-functioning, leads to a similar clinical phenotype. However, DAP12 is an integral subunit of other cell membrane-associated complex receptors with different functions. [2] Some clinical aspects of patients with DAP12 mutations might differ from those with TREM2 mutations in some circumstances. Septic shock would be an important example.
Septic shock is a leading cause of mortality and it was recently reported that DAP12/TREM1 complex may play a role in the development of septic shock. [3] This observation may lead to the development of new medicines and strategies for septic shock treatments.
For many years, we have been following a patient with Nasu-Hakola disease due to a DAP12 mutation [4] and have observed the clinical course of different infections. In one episode, after the introduction of anti-seizure drugs, the patient developed severe leucopenia and infection but not septic shock. She improved after adequate treatment.
We have considered the possibility that Nasu-Hakola patients--due to DAP12 mutations--could have abnormalities in septic shock mechanisms or even in other immunological responses, unlike Nasu-Hakola patients due to TREM2 mutations. Nasu-Hakola leads to death, generally as a consequence of urinary or pulmonary infections. [5] The final stages of Nasu-Hakola disease have not been reported, perhaps because until very recently, Nasu-Hakola disease was not considered to be associated with abnormalities in immunological mechanisms.
TREM2 or DAP12 deficiency might offer an opportunity to observe the role of these molecules in human immunology. Because Nasu-Hakola disease is rare, publication of isolated cases or short case-series reports should be encouraged and the course of infections, tumors, or other immunological abnormalities in these patients should be reported in detail. Such data would clarify the role of TREM2 or DAP12 in human immunology and the differences that may exist between these two forms of Nasu-Hakola disease.
The authors report no conflicts of interest.
References
1. Klunemann HH, Ridha BH, Magy L, et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 2005;64:1502-7.
1. Tomasello E, Vivier E. KARAP/DAP12/TYROBP: Three names and a multiplicity of biological functions. Eur J Immunol 2005 May 9; [Epub ahead of print].
3. Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 2001;410:1103-7.
4. Paloneva J, Manninen T, Christman G, et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 2002;71:656-62.
5. Bianchin MM, Capella HM, Chaves DL, et al. Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects. Cell Mol Neurobiol 2004;1:1-24.