Cd40cd154

Proven Lupus Treatment By Dr Gary Levin

Natural Lupus Treatment by Dr. Gary Levin

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The tumor necrosis factor receptor (TNFR) superfamily member CD40 is consti-tutively expressed on B cells, while its ligand CD154 (CD40 ligand, CD40L, gp39) is expressed on activated T and B cells. Mice deficient in CD40 or CD154 fail to develop functional germinal centers and display impaired class switching in response to T-dependent antigens [12, 13]. These phenotypes presumably reflect defective T-cell activation, although some studies suggest that activated B cells may express functional CD154 and therefore promote bystander autoreactive B-cell activation independent of T-cell help [14, 15]. Interestingly, CD40-

Fig. 5.1 T cell-dependent induction of autoimmune reactions in B cell-mediated autoimmune diseases. (A) Initiation of autoreactive B- and T-cell activation. Autoreactive T cells are activated when autoreactive B cells encounter antigen in the periphery, travel to lymphoid organs, and act as antigen-presenting cells (APC, 1A), or when professional APCs process and present autoantigens and/or other T-cell epitopes in the T-cell zone (1B). These activated T cells can then in turn activate the same or other auto reactive B cells via costimulatory molecules such as CD154 and/or CD28 (2A), or by secreting cytokines such as IFN-y and/or IL-4 (2B), which promote and/or augment B-cell activation and class switching. Activated autoreactive B cells then travel to the B-cell zone where they form germinal centers and undergo class switching, somatic hypermutation, and affinity maturation in the dark zone (DZ, 3). They escape apoptosis by receiving survival signals in the light zone (LZ, 4), either from activated T cells

(CD154, cytokines, etc.) or other APCs (BAFF, etc.), eventually exiting the follicular reaction as autoantibody-secreting plasma cells or memory B cells (5). Effective therapeutic manipulations in T-B interactions have involved both costimulatory and cyto-kine blockade, which presumably disrupt steps (2) and/or (4). (B) Amplification and epitope spreading of autoimmunity. Once activated, an autoreactive B cell specific for a determinant in an autoantigenic complex internalizes the antigens, processes them, and can present any epitope derived from this complex via MHC class II. T cells recognizing such an epitope become activated, upregulate costimulatory molecules and secrete cytokines, and can interact with and activate other B cells displaying the proper T-cell epitope on their surface, even though their BCRs recognize different B-cell epi-topes. As such, autoantigenic determinants expand and amplify during autoimmune inflammation.

Table 5.1 Costimulatory interventions in systemic lupus erythematosus3'.

System/ Intervention

Model

Anti-DNA

Glomerulonephritis

Ref.

CD40/CD154

Anti-CD154

(SWRxNZW) Fj

II

II

17

Anti-CD154

(NZB xNZW) F1

II

II

24, 200

Anti-CD154

Human SLE

I

I

25

CD154 -/-

MRL/lpr

II

II

22, 23

CD28

CD28 -/-

MRL/lpr

II

II

46

Anti-CD80

MRL/lpr

^

49

Anti-CD86

MRL/lpr

I

49

Anti-CD80/CD86

MRL/lpr

II

II

49

Anti-CD80

(NZBxNZW) Fj

^

^

52

Anti-CD86

(NZBxNZW) Fj

II

II

52

CD80 -/-

MRL/lpr

t

49

CD86 -/-

MRL/lpr

^

I

49

CD80/CD86 -/-

MRL/lpr

II

II

48

Anti-B7H

(NZBxNZW) Fj

II

II

50

CTLA4Ig

MRL/lpr

II

II

47

CTLA4Ig

(NZBxNZW) Fj

II

II

51, 201

CD137

Anti-CD137

MRL/lpr

II

II

58

Anti-CD137

(NZBxNZW) Fj

II

II

59

a) Effect of blocking antibodies or genetic deficiencies on the autoimmune syndromes of humans and mice with lupus. Significant versus mild reductions in the indicated disease parameters are indicated by jj and j, respectively; significant versus mild exacerbations in the indicated disease parameters are indicated by ^ and respectively; no significant difference in a disease parameter is indicated by a) Effect of blocking antibodies or genetic deficiencies on the autoimmune syndromes of humans and mice with lupus. Significant versus mild reductions in the indicated disease parameters are indicated by jj and j, respectively; significant versus mild exacerbations in the indicated disease parameters are indicated by ^ and respectively; no significant difference in a disease parameter is indicated by

CD154 interactions may also be required at least in part for the maintenance of T-cell tolerance [16].

Nonetheless, the dominant importance of CD40-CD154 in the pathogenic arm of autoimmune diseases has been repeatedly demonstrated in multiple studies (Tables 5.1 to 5.3). Several investigations have demonstrated abnormal expression of CD154 by both B and T cells in humans and mice with autoimmune diseases such as SLE [17-20], perhaps reflecting a primary defect in signaling molecules [21]. In addition, CD154-deficient MRL/lpr mice are generally protected from the development of IgG hypergammaglobulinemia, anti-DNA autoantibodies, and renal disease [22, 23], and anti-CD154 antibody treatment significantly delayed the development of anti-DNA antibodies and glomerulone-phritis in both lupus-prone (NZBxSWR) Fx and (NZB xNZW) Fx mice [17, 24], as well as in humans with SLE [25]. Similarly, intervention in the CD40-CD154 system protects against autoantibody and other autoimmune manifestations in

Table 5.2 Costimulatory interventions in myasthenia gravisa).

System/ Intervention

Modelb)

Anti-AchRb)

Myopathy

Ref.

CD40/CD154

Anti-CD154

Rat-EAMG

II

II

27

CD154 -/-

B6-EAMG

II

II

26

CD28

CD28 -/-

B6-EAMG

I

I

26

Anti-CD80

B6-EAMG

I

I

54

Anti-CD86

B6-EAMG

II

II

54

CD80 -/-

B6-EAMG

II

II

54

CD80/CD86 -/-

B6-EAMG

II

II

54

CTLA4Ig

Rat-EAMG

II

II

53

a) Effect of blocking antibodies or genetic deficiencies on the autoimmune syndromes of rodents with experimental myasthenia gravis. Significant versus mild reductions in the indicated disease parameters are indicated by [I and I, respectively.

b) AchR = acetylcholine receptor; B6 = C57BL/6; EAMG = experimental autoimmune myasthenia gravis.

Table 5.3 CD40/CD154 interventions in

other autoimmune

diseases a).

System/

Model/

Autoantibodies

End-organ

Ref.

Intervention

Background b)

disease

Anti-CD154

AO-ZP

II

II

28

Anti-CD154

AO-TX

II

II

29

Anti-CD154

Grave-scid

II

-

30

Anti-CD154

Hg

II

II

31

Anti-CD154

KRN

II

II

32

Anti-CD154

GVHD

II

II

33

Anti-CD154

Human SSc

II

ND

34

(in vitro)

CD154 Tg

C57BL/6

Tt

ff

35, 37

CD154-L929

C3H

n

TT

36

a) Effect of blocking antibodies or other genetic alterations within the CD40/ CD154 system on various autoimmune syndromes. Significant versus mild reductions in the indicated disease parameters are indicated by JJ and J, respectively; significant versus mild exacerbations in the indicated disease parameters are indicated by ff and f, respectively; no significant difference in a disease parameter is indicated by —.

b) AO-ZP = autoimmune oophoritis induced by zona pellucida peptides; AO-TX = autoimmune oophoritis induced by day-3 neonatal thymectomy; Grave-scid = Graves' thyroid tissue xenografted upon severe combined immunodeficient mice; GVHD = graft-versus-host disease; Hg = mercury-induced autoimmunity; KRN = K/B x N transgenic spontaneous arthritis mouse; SSc = systemic sclerosis (scleroderma); ND = not determined.

experimental autoimmune myasthenia gravis (EAMG) [26, 27], autoimmune oophoritis [28, 29], autoimmune thyroid disease [30], mercury-induced autoimmunity [31], the K/B x N immune-complex arthritis model [32], graft-versus-host disease [33], and systemic sclerosis [34]. Conversely, ectopic expression and/or prolonged exposure to CD154 signals can result in pathogenic autoantibody production and end-organ disease [35-37]. Thus, the CD40-CD154 system has emerged as a dominant target system in the pathogenesis and therapy of multiple autoimmune syndromes.

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