MMR: dendritic cells, intestines, measles, CMV, gangliosides

[Teresa Binstock]

	Date: Wed, 1 Apr 1998 09:53:38 -0700 (MST)
	From: Teresa Binstock <binstoct at essex.UCHSC.edu>
	To: AUTISM at maelstrom.stjohns.edu
	Subject: dendritic cells, intestines, measles, CMV, gangliosides

A recent Nature contains a fine review of dendritic cells and their
crucial roles in T-cell, B-cell, and cytokines responses (1). Another fine
review was presented in Blood (2). Among many fascinating aspects are: 
(i) a ganglioside link via how ceramides can "shut down antigen capture"
by dendritic cells (1, citing 3), thereby providing another route by which
a child's gangliosidosis-heterozygote status may impair immunity (4). 
(ii) "...maturation of DCs [dendritic cells] is crucial for the initiation
of immunity." (1)
(iii) "... MHC products and MHC-peptide complexes... are 10-100 times
higher on DCs than on other APCs like B cells and monocytes." (1).
(iv) a link to cytomegalovirus and to measles (cites 5-8, see also the
works of DE Griffin of Johns Hopkins, whose findings link both
vaccine-measles and natural measles to immune-system impairments).
(v) Keeping in mind that intestinal mucosal contain dendritic cells (1 and
references therein), note that the following quote mentions *measles
particles*, suggesting that vaccine and/or wildtype sources might affect
immunity:
	"Recent results paint a paradoxical picture in which DCs, instead
of inducing host resistance, provide a safe haven for several viruses.
Cells of the DC system may be hosting latent cytomegalovirus... For HIV-1
and measles, the consequences of DC infection are more overt: especially
upon interacting with memory T cells and activated T cells, they sustain
the production of many HIV-1, SIV and measles... particles. Measles turn
DCs into multinucleated cells, or syncytia, and suppresses dendritic-cell
and T-cell function... Syncytia are not just a sign of viral toxicity, as
is often assumed, but are also true virus factories... In vivo, infected
syncytia have been noted on the surfaces of mucosa-associated lymphoid
tissue... [eg, tonsils, intestines]. These so called lymphoepithelia
contain numerous memory B and T cells, as well as DCs that are chronically
exposed to maturation stimuli from the environment... But, rather than
battling with the infection, mature DCs [can] assist in its spreading..."
(1).

These facts about dendritic cells suggest that they may contribute
to intestinal effects of measles virus and measles-vaccine particles
and to various immune-impairing sequelae. 

Teresa

1. Banchereau J, Steinman RM. Dendritic cells and the control of
immunity. Nature 392.245-252 1998.

2. Hart DN. Dendritic cells: unique leukocyte populations which control
the primary immune response. Blood 90.9.3245-87 1997.

3. Sallusto F et al. Ceramide inhibits antigen uptake and presentation by
dendritic cells.
	  Journal of Experimental Medicine.  184(6):2411-6, 1996 Dec 1.
  Ceramides are intramembrane diffusible mediators involved in transducing
  signals originated from a variety of cell surface receptors. Different
  adaptive and differentiative cellular responses, including apoptotic cell
  death, use ceramide-mediated pathways as an essential part of the program.
  Here, we show that human dendritic cells respond to CD40 ligand, as well
  as to tumor necrosis factor-alpha and IL-1 beta, with intracellular
  ceramide accumulation, as they are induced to differentiate. Dendritic
  cells down-modulate their capacity to take up soluble antigens in response
  to exogenously added or endogenously produced ceramides. This is followed
  by an impairment in presenting soluble antigens to specific T cell clones,
  while cell viability and the capacity to stimulate allogeneic responses or
  to present immunogenic peptides is fully preserved. Thus,
  ceramide-mediated pathways initiated by different cytokines can actively
  modulate professional antigen-presenting cell function and
  antigen-specific immune responses.

4. Binstock, Teresa 1998. Hypothesis and primary citations presented
recently to autism list, findable via DejaNews.

5. Soderberg-Naucler C et al. Reactivation of latent human cytomegalovirus
by allogeneic stimulation of blood cells from healthy donors.
	Cell.  91(1):119-26, 1997 Oct 3.
  Reactivation of human cytomegalovirus (HCMV) results in severe disease in
  AIDS patients and immunocompromised patients receiving blood transfusions
  or organ or bone marrow grafts. Although the site of HCMV latency is
  unknown, blood cells have been implicated as a viral reservoir. In this
  study, we demonstrate HCMV reactivation in vitro from seven consecutive
  healthy donors through allogeneic stimulation of peripheral blood
  mononuclear cells (PBMCs). HCMV replication was detected at 17 days
  poststimulation, and virus was recovered after long-term culture from a
  macrophage expressing dendritic cell markers. Thus, these observations
  demonstrate that PBMCs harbor latent HCMV, which reactivates in a myeloid
  lineage cell upon allogeneic stimulation.

6. Fugier-Vivier I et al. Measles virus suppresses cell-mediated immunity
by interfering with the survival and functions of dendritic and T cells.
	  Journal of Experimental Medicine.  186(6):813-23, 1997 Sep 15.
  Secondary infections due to a marked immunosuppression have long been
  recognized as a major cause of the high morbidity and mortality rate
  associated with acute measles. The mechanisms underlying the inhibition of
  cell-mediated immunity are not clearly understood but dysfunctions of
  monocytes as antigen-presenting cells (APC) are implicated. In this
  report, we demonstrate that measles virus (MV) replicates weakly in the
  resting dendritic cells (DC) as in lipopolysaccharide-activated monocytes,
  but intensively in CD40-activated DC. The interaction of MV-infected DC
  with T cells not only induces syncytia formation where MV undergoes
  massive replication, but also leads to an impairment of DC and T cell
  function and cell death. CD40-activated DC decrease their capacity to
  produce interleukin (IL) 12, and T cells are unable to proliferate in
  response to MV-infected DC stimulation. A massive apoptosis of both DC and
  T cells is observed in the MV pulsed DC-T cell cocultures. This study
  suggests that DC represent a major target of MV. The enhanced MV
  replication during DC-T cell interaction, leading to an IL-12 production
  decrease and the deletion of DC and T cells, may be the essential
  mechanism of immunosuppression induced by MV.

7. Grosjean I... Banchereau J et al. Measles virus infects human
dendritic cells and blocks their allostimulatory properties for CD4+ T
cells.
	  Journal of Experimental Medicine.  186(6):801-12, 1997 Sep 15.
Abstract
  Measles causes a profound immune suppression which is responsible for the
  high morbidity and mortality induced by secondary infections. Dendritic
  cells (DC) are professional antigen-presenting cells required for
  initiation of primary immune responses. To determine whether infection of
  DC by measles virus (MV) may play a role in virus-induced suppression of
  cell-mediated immunity, we examined the ability of CD1a+ DC derived from
  cord blood CD34+ progenitors and Langerhans cells isolated from human
  epidermis to support MV replication. Here we show that both cultured CD1a+
  DC and epidermal Langerhans cells can be infected in vitro by both vaccine
  and wild type strains of MV. DC infection with MV resulted within 24-48 h
  in cell-cell fusion, cell surface expression of hemagglutinin, and virus
  budding associated with production of infectious virus. MV infection of DC
  completely abrogated the ability of the cells to stimulate the
  proliferation of naive allogeneic CD4+ T cell as early as day 2 of mixed
  leukocyte reaction (MLR) (i.e., on day 4 of DC infection). Mannose
  receptor-mediated endocytosis and viability studies indicated that the
  loss of DC stimulatory function could not be attributed to the death or
  apoptosis of DC. This total loss of DC stimulatory function required viral
  replication in the DC since ultraviolet (UV)-inactivated MV or UV-treated
  supernatant from MV-infected DC did not alter the allostimulatory capacity
  of DC. As few as 10 MV- infected DC could block the stimulatory function
  of 10(4) uninfected DC. More importantly, MV-infected DC, in which
  production of infectious virus was blocked by UV treatment or
  paraformaldehyde fixation, actively suppressed allogeneic MLR upon
  transfer to uninfected DC-T-cultures. Thus, the mechanisms which
  contribute to the loss of the allostimulatory function of DC include both
  virus release and active suppression mediated by MV-infected DC,
  independent of virus production. These data suggest that carriage of MV by
  DC may facilitate virus spreading to secondary lymphoid organs and that MV
  replication in DC may play a central role in the general immune
  suppression observed during measles.

8. Schnorr JJ et al. Induction of maturation of human blood dendritic cell
precursors by measles virus is associated with immunosuppression.
  	Proceedings of the National Academy of Sciences of the United
	States of America.  94(10):5326-31, 1997 May 13.
  As well as inducing a protective immune response against reinfection,
  acute measles is associated with a marked suppression of immune functions
  against superinfecting agents and recall antigens, and this association is
  the major cause of the current high morbidity and mortality rate
  associated with measles virus (MV) infections. Dendritic cells (DCs) are
  antigen-presenting cells crucially involved in the initiation of primary
  and secondary immune responses, so we set out to define the interaction of
  MV with these cells. We found that both mature and precursor human DCs
  generated from peripheral blood monocytic cells express the major MV
  protein receptor CD46 and are highly susceptible to infection with both MV
  vaccine (ED) and wild-type (WTF) strains, albeit with different kinetics.
  Except for the down-regulation of CD46, the expression pattern of
  functionally important surface antigens on mature DCs was not markedly
  altered after MV infection. However, precursor DCs up-regulated HLA-DR,
  CD83, and CD86 within 24 h of WTF infection and 72 h after ED infection,
  indicating their functional maturation. In addition, interleukin 12
  synthesis was markedly enhanced after both ED and WTF infection in DCs. On
  the other hand, MV-infected DCs strongly interfered with mitogen-dependent
  proliferation of freshly isolated peripheral blood lymphocytes in vitro.
  These data indicate that the differentiation of effector functions of DCs
  is not impaired but rather is stimulated by MV infection. Yet, mature,
  activated DCs expressing MV surface antigens do give a negative signal to
  inhibit lymphocyte proliferation and thus contribute to MV-induced
  immunosuppression.						     eof