Advances in the Canine Cranial Cruciate Ligament, 2nd edition

Role of Synovial Immune Responses in Stifle Synovitis 103

dendritic cells (Faldynaet al. 2004; Lemburg
et al. 2004; Klockeet al. 2005; Muiret al. 2005;
Muiret al. 2007a; Muiret al. 2009; Muiret al.
2011). The proportion of T lymphocytes within
synovial tissues is increased in dogs with CR
compared with samples from healthy dogs
(Faldynaet al. 2004). Expression of the T-cell
antigen receptor complex is also increased in
synovium and synovial fluid in affected dogs
(Muiret al. 2009). While lymphocytes play a
key role in antigen-specific immunity, activated
macrophages and their inflammatory products
play a key role in innate immunity and the
pathogenesis of tissue inflammation.

Antigen-specific immune responses

within joint tissues

The upregulation of T lymphocytes within
joints is a key pro-inflammatory feature of
arthritis, and also occurs in joint diseases that
have traditionally been considered to be asso-
ciated with minimal inflammation (Sakkas &
Platsoukas 2007). The identification of large
populations of lymphocytes within synovial tis-
sues of dogs with CR suggests that the distur-
bance of antigen-specific immune responses is
an important component of the disease mech-
anism. A MHC class II genetic risk has been
identified in many immune-mediated joint dis-
eases in human beings. Although immuno-
genetic risk for inflammatory arthritis exists in
dogs (Ollieret al. 2001), MHC class II immuno-
genetic risk with canine CR was not confirmed
in a recent study (Clementset al. 2011). How-
ever, MHC class I immunogenetic association
has not been investigated in dogs with CR to
date.
At the present time, the explanatory mech-
anism for chronic stifle synovitis in dogs with
CR remains a critical but unanswered question.
Several studies have explored the hypothesis
that neo-epitopes of type I and type II colla-
gen may be important in this regard (Niebauer
et al. 1987; de Bruinet al. 2007a,b) (see Chap-
ter 11). Collectively, these studies have not con-
firmed that neo-epitopes of collagen are the pri-
mary immunological trigger in dogs with CR,
and further investigations are needed.
The translocation of bacterial material into
the stifle joint is a common event in dogs (Muir

et al. 2007b). A polymicrobial population of

bacteria, many of which that are not recog-

nized joint pathogens, is typically present, par-

ticularly Gram-negative organisms (Muiret al.

2010). Similar microbial populations are found

in human arthritic joints (Kempsellet al. 2000). It

seems most likely that the translocation of small

amounts of bacterial material to the stifle syn-

ovium from the circulation may act to maintain

synovial inflammation, but not necessarily ini-

tiate disease (Bhandalet al. 2013).

Innate immune responses within joint

tissues

Although antigen-specific immune responses

within the stifle have a role in the development

of synovial inflammation in dogs with CR,

innate immune responses within the stifle

synovium are also likely important. Pattern-

recognition receptors (PRR) are expressed

by leukocytes and epithelial cells, and are

used by the innate immune system to detect the

presence of infection (Akiraet al. 2006). The acti-

vation of PRR contributes to disease pathology

in inflammatory and autoimmune conditions

(e.g., Bryant & Fitzgerald 2009). The activation

of PRR, such as toll-like receptor (TLR) and

nucleotide-binding oligomerization domain

(NOD) -containing proteins leads to the acti-

vation of nuclear factor kappa B (NFκβ)and

upregulation of immune response genes and

pro-inflammatory cytokines. Innate immune

responses to PRR also regulate subsequent

adaptive immune responses via dendritic cell

signaling (Iwasaki & Medzhitov 2015). Defec-

tive PRR function has been implicated in vari-

ous chronic inflammatory conditions, such as

Crohn’s disease in human beings and perianal

fistulae in dogs (Houseet al. 2008). Analysis of

synovial fluid cells from dogs with CR suggests

that expression of TRAP is increased relative to

that in healthy dogs and dogs with osteoarthri-

tis (Figure 13.3A) (Muiret al. 2007a). Higher

expression of TLR-2 in arthritic joints was also

been found (Figure 13.3B) (Muiret al. 2007a).

Increased expression of complement compo-

nent 3, CXCL8, which is primarily expressed by

macrophages, and intercellular cell adhesion

molecule-1 (ICAM-1), is also found in the

synovium of dogs with CR (El-Hadiet al. 2012;