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REVIEW ARTICLE
Autoimmune Neutropenia
By Kaushik A. Shastri and Gerald L. Logue
There have been several new developments in the field of
autoimmune neutropenia over the past decade. Neutropenia
caused by antibodies directedagainst granulocyte precursor
cells, the oligoclonal nature of antineutrophil antibodies,
and the expanding knowledge of neutrophilantigens, par-
ticularly in relationship to autoantibodies,are exciting new
areas of investigation. Knowledge has also been advanced
in the effector mechanismsof neutrophil autoantibodies and
the effect of autoantibodieson the neutrophil function. In
addition, some clinical syndromes of immune neutropenia
M ECHANISMS INVOLVED in the pathogenesis of au-
toimmune neutropenia are better defined in some
instances such as the anti-NA 1-induced neutropenia of
infancy’ or some drug-induced neutropenias.24 In other dis-
eases such as Felty’s syndrome, several mechanisms have been
proposed to explain the observed neutropenia, such as ex-
cessive neutrophil marginati~n,~ destruction of neutrophils
by autoantibodies or immune c ~ m p l e x e s ,and
~ . ~ the hema-
topoietic defects due to suppressor T celk8-10Importantly,
more than one mechanism may be responsible in a given
situation. In diseases in which antineutrophil antibodies are
frequently encountered, such as T-y lymphoproliferative
or systemic lupus erythemato~us,’~ the antibodies
might still represent an epiphenomenon rather than the pri-
mary pathogenic process. The following describes the role
and nature of autoantibodies to neutrophils in autoimmune
neutropenia, and the potential targets for such autoantibodies.
Eflector mechanisms of antineutrophil antibodies.
Lawrence et a l l 4 and Simpson and Ross15administered rabbit
anti-guinea pig neutrophil antiserum to guinea pigs and ob-
served a prompt disappearance of circulating neutrophils.
Histologic examination of the bone marrow and lymphoid
organs showed neutrophils encased within phagocfic vac-
uoles in macrophages.” These early observations indicated
that phagocytosis of sensitized neutrophils is an important
mechanism of neutropenia after exposure to antineutrophil
antibodies.
Human autoimmune antineutrophil antibodies generate
opsonic activity, which can be quantitated.l67I7However, the
amount of antineutrophil antibody detected in patients with
autoimmune neutropenia does not correlate with the degree
of neutropenia.I8 This apparent lack of correlation can be
partly explained by the ability of some autoantibodies to ac-
From the Department of Medicine and Division of Hematology,
State University of New York at Buffalo and Department of Veterans
Affairs Medical Center, Buffalo,NY.
Submitted December 3, 1991; accepted December 4, 1992.
Supported in part by grants from the Research Service of the De-
partment of Veterans Affairs and the Richard E. Wahle Research
Fund of the State University of NY at Buffalo.
Address reprint requests to Gerald L. Logue, MD, Chief of Staff;
D. V.A.Medical Center, 3495 Bailey Ave, Buffalo, NY 14215.
0 1993 by The American Society of Hematology.
0006-4971/93/8108-0027$3.00/0
1984
have been better defined over the past decade, such as
autoimmune neutropeniaof infancy and chronic idiopathic
neutropenia in adults. The past decade also saw interesting
developments in the treatment of immune neutropenia,
particularly in the use of gammaglobulin preparations and
more recently in the advent of hematopoietic growth fac-
tors. This review focuses on these newer aspects of au-
toimmune neutropenia.
0 1993 by The American Society of Hematology.
tivate complement. In contrast to red blood cells, the nu-
cleated human granulocytes are resistant to the lytic effects
of complement.” However, sublytic complement activation
with deposition of C3 can also serve the opsonic function.
In a study by Rustagi et a1,” antigranulocyte antibodies pres-
ent in sera of patients with Felty’s syndrome were able to fix
C3 on donor granulocytes. The complement-fixing ability
was present in the monomeric IgG fraction. Similar studies
on patients with systemic lupus erythematosus showed a cor-
relation between the degree of neutropenia and the C3 fixing
ability of the antibodies.” In a study on sera from patients
with T-r lymphoproliferative disease, the majority of neu-
tropenic patients had complement-fixing antineutrophil an-
tibodies.’* Thus, the complement-fixing ability of antineu-
trophil antibody is an important determinant of its pathogenic
potential.
Binding of immune complexes to neutrophil Fc or com-
plement receptors can also lead to increased clearance of
neutrophils. Breedveld et a1’: using Felty’s syndrome-derived
immune complexes injected into mice, and Caligaris-Cappio
et al,23 using idiopathic neutropenia-derived immune com-
plexes injected into rabbits, observed neutropenia in the ex-
perimental animals. The results of both studies suggested that
immune complexes led to granulocyte sequestration in pa-
tients with these two syndromes. Some serologic studies have
also questioned the presence of granulocyte-specific auto-
antibodies in Felty’s syndrome. Petersen and WiikZ4were
unable to show neutrophil binding of F(ab)2 fragments of
IgG of patients with Felty’s syndrome. Unfortunately, they
did not use known granulocyte alloantibodies or autoanti-
bodies as positive controls. Goldschmeding et aIz5found that
polyethylene glycol (PEG) treatment of Felty’s syndrome sera
led to reduction in IgG antineutrophil antibody levels, pre-
sumably by removing the contribution of IgG-containing
immune complexes. PEG treatment, on the other hand,
completely eliminated IgM and IgA binding to neutrophils.
However, these investigators also stressed the importance of
the infrequently found antibody-dependent lymphocyte-me-
diated granulocytotoxicity (ADLG) in defining the true an-
tibody positivity. More recently, the same group suggested a
pathogenic role, in systemic autoimmune diseases, for biva-
lent immune complexes not detected by serum C l q binding
assays.26In a study of sera from 19 patients with Felty’s syn-
drome, Starkebaum et a16 found that both soluble immune
complexes and neutrophil-reactive IgG contributed to the
Blood, Vol81, No 8 (April 15). 1993: pp 1984-1995
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
AUTOIMMUNE NEUTROPENIA
elevated granulocyte-binding IgG. The soluble immune
complexes can also lead to complement activation, adherence
of neutrophils to other leukocytes, decreased neutrophil
phagocytic ability, or decreased neutrophil chemotaxis.6
Another important variable in the pathogenic effect of an-
tibody is whether the antigen is also present on the myeloid
precursor cells. Because maintaining a normal neutrophil
count requires a high marrow output, an antibody reacting
with early precursors and interfering with marrow production
can have a dramatic effect on peripheral neutrophil levels.
Levitt et alz7proposed the term “pure white cell aplasia” to
represent antibody-mediated autoimmune inhibition of
granulopoiesis in some patients with isolated neutropenia and
profound reduction of myeloid precursors in the bone mar-
row. Thus, pure white blood cell aplasia would be analogous
to the previously defined entity of pure red blood cell aplasia.
Harmon et aIz8described a patient with severe neutropenia
and myeloid hypoplasia whose serum deposited IgG on my-
elocytes and promyelocytes. In another study, sera from three
patients with selective myeloid hypoplasia bound s i d c a n t l y
more IgG to cells of the myeloid precursor cell line HL-60
than did the control sera, whereas IgG binding to mature
granulocytes was not significantly different.29 This finding
was associated with a marked reduction in bone marrow
granulocyte precursors.
In addition to neutropenia, neutrophil autoantibodies may
adversely affect the function of neutrophils, producing qual-
itative defects in the neutrophils. Polyclonal and monoclonal
antibodies raised against human neutrophils have induced
functional defects in human neutrophils. Boxer and S t ~ s s e l , ~ ~trophil dysfunction in the absence of neutropenia, as pre-
in their in vitro studies, demonstrated that neutrophils sen-
sitized with rabbit antihuman leukocyte serum showed im-
pairment in COz production from I4C glucose after the ad-
dition of polystyrene particles. Some monoclonal antibodies
to the CDl lb complex can induce, in normal neutrophils,
defects similar to those seen in neutrophils of patients with
leukocyte adhesion defect (LAD).3’ The neutrophils from
patients with LAD are genetically deficient in CD11/CD18
complex. Interestingly, other monoclonal antibodies to the
CD11/CD18 complex interfere with both CDl 1/CDl %de-
pendent and -independent neutrophil functions. The later
effect appears to be mediated by cyclic adenomonophosphate
(CAMP),as shown by direct measurements of CAMP levels.31
Another monoclonal antibody to human granulocyte (G2)
was capable of a dose-dependent inhibition of oxygen con-
sumption of human granulocytes after stimulation by a va-
riety of stimulants, including aggregated Ig and zymosan.32
The neutrophil autoantibodies found in patients with im-
mune neutropenia have also been shown to interfere with
neutrophil function. In the study by Hartman and Wright,33 highly purified by repeated absorption to red blood cells and
IgG from one of their patients with recurrent infections con-
sistently showed abnormal aggregation-disaggregation re-
sponse upon stimulation by formyl peptide chemotactic fac-
tors in vitro. Such a finding raises the possibility that
autoantibodiesto neutrophil adhesion molecules may some-
times interfere with normal neutrophil function and amplify
the risk of infection associated with neutropenia. Davis et
a134showed reduced superoxide radical production in neu-
1985
trophils from patients with Felty’s syndrome. The reduction
in neutrophil function correlated with the serum levels of
granulocyte-binding antibodies in their patients. The same
group also showed that the plasma from Felty’s syndrome
patients reduced superoxide generation of coincubated nor-
mal gran~locytes.~’ Macey et a136quantified neutrophil ox-
idative burst and uptake of staphylococcus aureus by flow
cytometry, using cells of patients with autoimmune neutro-
penia. The rate of bacterial uptake in the autoimmune neu-
tropenia patients was significantly reduced when compared
with that of the controls.There was also a significant reduction
in the ability of neutrophils from neutropenia patients to
respond to opsonized bacteria or to bind monoclonal anti-
bodies to Fc receptors. An important caveat of these studies
is the difficulty in obtaining appropriate controls with a cor-
responding degree of neutrophil immaturity. The study of
Davis et a134used, as controls, neutrophils from patients with
gold induced neutropenia, whereas the study of Macey et a136
did not address this issue. In addition, neutrophils from im-
mune neutropenic patients may have shed or internalized
surface antigen receptors in response to prior antibody bind-
ing. Weitzman et a137found serum autoantibodies to neu-
trophils in approximately half the patients with Grave’s dis-
ease. These antibodies appeared to have specificity for
neutrophil thyrotropin (TSH) receptors, because TSH could
displace their binding. While not presenting direct data, these
investigators speculate that antibody binding to neutrophil
TSH receptors could interfere with neutrophil CAMP pro-
duction. Neutrophil autoantibodies can also produce neu-
sented by Kramer et al.38They described a non-neutropenic
patient with recurrent staphylococcal skin infections whose
neutrophils had an isolated motility defect. Other measures
of neutrophil function, including phagocytosis and generation
of superoxide anion, were normal. The motility defect could
be induced in normal granulocytes by in vitro incubation
with small amounts of IgG purified from the patient.
Autoimmunity of restricted clonal origin. A fundamental
question in understanding the pathophysiology of immune
neutropenia is how the immune tolerance is breached. There
are generally two major pathways to allow this immune dis-
regulation. In the first, immune reactions to a recognizably
foreign antigen are produced and the immune response cross-
reacts with self-antigens. A classic example of this is cold
reacting anti-red blood cell antibodies (cold agglutinins) pro-
duced as a reaction to infection with mycoplasmal pneu-
monia. In this disorder, cold reactive autoantibodies of poly-
clonal origin are produced.39 Cold agglutinin antibodies,
because of their temperature-dependent cell binding, can be
thus immunochemically characterized. The autoantibodies
found in association with mycoplasma pneumonia contain
a mixture of K and X light chain-bearing Igs.
The second mechanism of autoimmunity involves loss of
suppression of a clone of cells that are able to react with self-
antigens. With immune disregulation in autoimmune dis-
eases, these clones proliferate and produce pathologic anti-
bodies. An example of this is the chronic cold agglutinin
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
1986
syndrome, in which cold reactive IgM antibodies are pro-
duced against human red blood cells. In contrast to the cold
agglutinin antibodies produced as the result of a mycoplasma
infection, the autoantibodies of the chronic cold agglutinin
syndrome are generally monoclonal, specificallyof one light-
chain type. The clinical manifestations of these two different
types ofcold agglutinins are considerably different. The poly-
clonal antibodies, presumably produced by cross-reactivity,
produce a milder self-limited disease and rarely an overt he-
molytic anemia. In contrast, the red blood cell autoantibodies
in the chronic cold agglutinin syndrome tend to increase pro-
gressively and are often associated with manifestations of ei-
ther acute intravascular hemolysis or acrocyanosis. The
chronic cold agglutinin syndrome is frequentlyassociatedwith
other underlying diseases, such as lymphomas.
There is mounting evidence that autoimmune antibodies
in diverse diseases are of restricted clonal origin. Knight et
al,40in their study of thyroid-stimulating autoantibodies in
patients with Grave’s disease, found them to consist of single
light chains, predominantly of X isotype. In a recent study
of patients with idiopathic thrombocytopenic purpura, similar
clonal B-cell expansion was found in most patient^.^' Ad-
ditionally, none of the patients in this study developed clinical
manifestations of lymphoma on subsequent follow-up.
Shastri et d4*studied the light chain composition of gran-
ulocyte-binding Igs of patients with malignant as well as non-
malignant disorders, and measured the K and the X light chain-
bearing granulocyte-binding Igs. Serum granulocyte-binding
IgG, IgM, and the light chain composition of granulocyte-
binding Igs were measured in 58 adult subjects, including 8
normal individuals, 6 with Felty’s syndrome, 6 with chronic
idiopathic neutropenia, 32 with B-cell chronic lymphocytic
leukemia (CLL), and 6 with multiple myeloma. Eight of the
12 patients with immune neutropenia and no underlying
neoplastic disorder had light chain-restricted granulocyte-
binding Igs (5 with chronic idiopathic neutropenia and 3 with
Felty’s syndrome). These studies suggest that clonal expansion
of lymphoid cells, either in the malignant or nonmalignant
autoimmune diseases, can lead to light chain-restricted neu-
trophil-binding autoantibodies. Light chain restriction of
granulocyte-binding Igs was largely (76%)of X isotype. Similar
observations have been made for thyroid-stimulating auto-
antibodies, which were primarily of X light chain type.40This
is not surprising, because genes linked to the loci for the Ig
X constant region may influence the susceptibilityto autoim-
mune diseases such as rheumatoid arthritis and Grave’s dis-
e a ~ e . Study
4 ~ ~ of~~restriction of target-bound Igs may hint to
closer ties between the genes linked to the production of X
light chains and the susceptibility to autoimmune neutro-
penia.
Antigen targets in immune neutropenia. Several neutro-
phil-specific antigens have been described in the past 20 years
based on serologic techniques using alloantibodies and more
recently with the use of monoclonal antibodies. The antigenic
targets for neutrophil autoantibodies are presently an area of
considerable interest.
Autoantibodies to the neutrophil-specific antigens of the
NA system have been associated with autoimmune neutro-
SHASTRI AND LOGUE
penia. In Lalezari et al’s” series of patients with autoimmune
neutropenia of infancy, neutrophil antibodies were demon-
strated in 119 of 121 patients. Ten percent of these antibodies
had a specificity for NAl or NA2. Bux et a145noted a signif-
icant association between autoimmune neutropenia in infants
due to NAl specific antibodies and HLA-DR2. Nineteen of
26 infants presenting with autoimmune neutropenia of in-
fancy and NAl autoantibodies possessed DR2 antigen,
whereas only one of six children with non-NA 1-specific au-
toantibodies was DR2 positive. All DR2-negative patients
were positive for DRw6. The investigators speculate that the
spontaneous recovery seen in autoimmune neutropenia of
infancy, coincides with the full development of suppressor
T-cell function at about 3 years of age. NAl-specific auto-
antibodies have also been described in primary biliary cir-
rhosis!6 Antibodies to NAl and NA2 are also important in
other clinical conditions, including leukocyte-mediated
transfusion reactions and alloimmune neonatal neutro-
penia!’ Recently, relationships between some of these an-
tigens and the known neutrophil surface glycoproteins have
been recognized. The neutrophil antigens NA 1 and NA2 have
been identified as glycosylated isoforms of neutrophil Fc re-
ceptor 111, and NB 1 antigen has been shown to reside on the
58- to 64-Kd glycoprotein present on the surface of neutro-
phils, and in secondary Thus, alloantibodies and
autoantibodies directed against functional neutrophil mem-
brane receptors are associated with overt clinical disease.
Generally, the analysis of antigen targets of neutrophil au-
toantibodies is difficult because these antibodies are present
in low titer and bind to their targets with low avidity. Rothko
et alSz performed immunoblotting studies of neutrophil
membrane antigens using sera from patients with autoim-
mune neutropenia. They found that 16 ofthe 17 sera showed
discrete bands in the molecular weight range of 30 to 1 12.
The 3 patients with Felty’s syndrome reacted with an anti-
genic target of 80 to 84 Kd. In comparison, previous studies
done with monoclonal antibodies showed reaction with
structures of higher molecular weights. Based on this, they
concluded that autoantibodies do not appear to react against
any of the previously identified surface structures of neutro-
phil such as CR 1, X Hapten, leukocyte function-associated
(LAF) group, lactosylceramide, or C3bi receptor.
Hartman et a133have identified autoantibodies to specific
neutrophil antigen targets. Using an immunobead antigen
capture assay, they detected specific autoantibodies to the
neutrophil adhesion glycoprotein complex CD 1 1b/CD 18 in
the sera of 7 of 50 patients with autoimmune n e ~ t r o p e n i a . ~ ~
This technique depends on antigen preservation after deter-
gent solubilization of sensitized neutrophils and can detect
immune complexes as well the specific antibody. They used
sera from normal donors and non-neutropenic patients with
rheumatoid arthritis and systemic lupus erythematosus as
controls. Sera of 2 of 2 1 non-neutropenic patients with rheu-
matoid arthritis had anti-CD 1 1/CD 18 levels that were slightly
greater than a 95% confidence interval above the mean of
normal values. The importance of antibodies against CD 1 1b/
CD 18 antigen complex has been discussed in the earlier sec-
tion in this review. The same group, using immunoblotting
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
AUTOIMMUNE NEUTROPENIA
of electrophoretically separated human neutrophil-associated
proteins, detected the presence of an antibody to a 43-Kd
protein in sera of 8 of 36 patients with autoimmune neutro-
~ e n i aThey
. ~ ~ indirectly identified this protein as actin. Two
actin-specific monoclonal antibodies bound to the 43-Kd
protein. In addition, a rabbit antiactin serum not only bound
to the same protein but expressed antineutrophil activity.
The purified human antiactin IgG, prepared by affinity chro-
matography from serum oftheir index patient, expressed an-
tineutrophil antibody activity. Presence of low titer antiactin
antibodies have been described in some normal individual^.^^
Antiactin antibodiesalso occur in patients with chronic active
hepatitis and alcoholic liver disease, and with other autoim-
mune disorders such as systemic lupus erythematosus (SLE),
Sjogren’s Syndrome, and myesthenia gravis.53It is unclear
whether the antiactin antibodies represent a generalized im-
mune response to free actin released because of cell injury,
or a specific immune response relevant to the pathogenesis
of diseases in which these autoantibodies are found.
Because antineutrophil antibodies are present in approx-
imately 50% of patients with SLE,I3a disorder characterized
by antinuclear antibodies, the idea of cross-reactive antibodies
that could react with both cell surface protein and nuclear
components is appealing. Rekvig and Hannestad” found that
certain antinuclear antibodies could react with the surface of
lymphocytes, monocytes, and polymorphonuclear leukocytes.
Because these cells possess receptors for DNA,56it is possible
that DNA released by injured cells is taken up by leukocytes
and targeted by antinuclear antibodies.
Answers regarding the origin of neutrophil autoantibodies
will be forthcoming with the understanding of the mecha-
nisms of systemic autoimmune disorders such as rheumatoid
arthritis and SLE. The source of immunization might be the
release of autoantigens after cellular injury or alteration of
antigens such as after exposure to drugs such as procainamide.
The autoimmunity may also result from molecular mimicry
of exogenous microbial proteins in a setting of genetic pre-
disposition. All these are areas of intense investigation.
SELECTED NEUTROPENIC SYNDROMES
Chronic idiopathic neutropenia in adults. In a subset of
patients referred for evaluation of chronic neutropenia, no
underlying cause is found. Kyle and Linman5’ described a
series of 15 such patients and published a further report on
their natural history.58All but one of the patients were female,
one patient had an associated anemia judged to be due to
menorrhagia, and two patients had serum leukoagglutinins.
With up to 31 years of follow-up (median, 15 years), no pa-
tient manifested an initially occult primary etiology, six pa-
tients ultimately developed neutrophil counts exceeding l X
109/L, and no patient experienced unexpected infectious
complications. Dale et a15’ reported 29 patients with idio-
pathic chronic neutropenia, ofwhich 22 were female. Fifteen
had mild anemia, including 1 patient with autoimmune he-
molytx anemia and 1 with thrombocytopenia.Of 16 patients
tested, only 1 patient with autoimmune hemolytic anemia,
who had received multiple transfusions, had detectable an-
tineutrophil antibodies. A pattern of recurrent cutaneous and
1987
upper and lower respiratory tract infections was noted, with
few serious infections and no deaths. Four patients were
treated with corticosteroidswith apparent benefit. Greenberg
et a160 reported a series of 41 adults with unexplained neu-
tropenia; no patient had a palpable spleen, history of exposure
to a drug or toxin known to lead to neutropenia, clinical or
serologic evidence of systemic illness, or a family history of
neutropenia. All had normal marrow cellularity, and 27%
showed a myeloid maturation arrest. Four patients had mild
anemia, and one had thrombocytopenia. Antineutrophil an-
tibodies were sought using an opsonic assay in 19 patients,
and were found in 3. Twenty-seven percent of patients had
infectiouscomplications;the incidencewas greater in patients
with fewer than 0.5 X 109/Lgranulocytes. Patients had nor-
mal marrow colony-forming units-granulocyte-macrophage
(CFU-GM) by soft agar assay, but the patients with severe
neutropenia appeared to have decreased marrow granulocyte
colony-stimulating activity.
Logue et a16’ studied sera from 121 adult patients with
chronic idiopathic neutropenia for IgG, IgM, and comple-
ment-fixing antineutrophil antibodies. Of the 12 1 patients,
7 1 had isolated neutropenia, whereas 50 had neutropenia
combined with either anemia and/or thrombocytopenia.
Among the 7 1 patients with isolated neutropenia, there were
5 1 females (72%),compared with 28 females (56%)in the 50
patients with combined hemocytopenias. In contrast to the
studies described above, 36% of their sera had antineutrophil
antibodies, suggesting an immune mechanism of neutropenia
in a subset of patients with chronic idiopathic neutropenia.
In this study, the investigatorscould characterize two distinct
subgroups of patients, namely those patients without other
hemocytopenias and those with neutropenia combined with
anemia and/or thrombocytopenia. The patients with com-
bined hemocytopenias were significantly older, and were more
likely to have splenomegaly (34% v 8.4%) and develop in-
fectiouscomplications of their illness (24%v 14%).The com-
bined cytopenia group not only had a higher incidence of
antineutrophil antibodies (43% v 32%), but the antibodies,
when present, were more Likely to fix complement on gran-
ulocytes. Thus, in chronic idiopathic neutropenia, as in SLE,
complement fixing antineutrophil antibodies are associated
with more severe disease manifestations. Bone marrow ex-
amination typically showed normal to slightly hypercellular
marrow, with a myeloid maturation arrest at the myelocyte
and metamyelocyte stages. Antineutrophil antibodies did not
correlate with the bone marrow morphology in the above
study.
T-y lymphocytosis. Leukemia of large granular lympho-
cytes (LGL) is a syndrome with associated immune neutro-
penia, identified over the past decade. These patients generally
present with severe neutropenia and varying degrees of large
granular lymphocytosis. These lymphocytes show surface
markers of cytotoxic/suppressor T cells. Bone marrow infil-
tration with LGL and moderate splenomegalyare frequently
present. Other hematologic abnormalities seen in these pa-
tients include cyclic neutropenia, pure red blood cell aplasia,
and thrombocytopenia.62Whereas the precise mechanism of
neutropenia in this disease is unclear, several groups of in-
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
1988
vestigators have identified antineutrophil antibodies in these
patients. Loughran et all’ described three patients with clonal
chromosomal abnormality of leukemic lymphocytes, all of
whom had high levels of neutrophil-reactive IgG. Two of the
three patients had associated thrombocytopenia with in-
creased levels of platelet associated IgG and one patient had
Coomb’s positive hemolytic anemia with an anti-E antibody.
Their studies suggested that antibody-mediated peripheral
destruction of neutrophils was the cause of neutropenia rather
than cell-mediated suppression of granulopoiesis. In a study
by Rustagi et all2 on sera from 57 patients with lymphopro-
liferative diseases, large granular lymphocytic leukemia had
the highest prevalence of granulocyte-binding antibodies.
Four of the five granulocytopenic patients’ sera produced
significantly greater IgG binding to target granulocytes. Serum
from the IgG antineutrophil antibody-negative neutropenic
patient demonstrated increased amount of C3 to target neu-
trophils. This complement-activating ability was present in
the monomeric IgG fraction by Sephacryl sizing chromatog-
raphy.
T-y lymphocytosis is frequently associated with other au-
toimmune diseases. When associated with rheumatoid ar-
thritis, this syndrome resembles Felty’s syndrome. Saway et
a163found large granular lymphocyte proliferation in 6 of
1,053 patients with rheumatoid arthritis, all of whom had
neutropenia. They emphasized that large granular lympho-
cyte proliferation should be distinguished from Felty’s syn-
drome, in neutropenic patients with rheumatoid arthritis.
The presence of large granular lymphocytosis in peripheral
blood, bone marrow infiltration with LGL, and immuno-
phenotypic studies are all helpful in making such a distinction.
ANTIBODY TESTING IN PATIENTS WITH SUSPECTED
IMMUNE NEUTROPENIA
In general, detecting antineutrophil antibodies directly on
the patients’ neutrophils is difficult because the neutrophils
are fragile, tend to aggregate in vitro, and release autolytic
enzymes on handling. In neutropenic patients, the neutrophils
are not only in small numbers but are also probably more
immature than cells obtained from normal controls or non-
neutropenic patients with other immunologic disorders. The
neutrophils recovered from patients with autoimmune neu-
tropenia are also likely to have major membrane alterations
after release from marrow. Specifically, the cells may have
shed or internalized membrane antigensand/or receptors after
interaction with autoantibody. Whereas flow cytometric
analysis of granulocyte immunofluorescence has greatly en-
hanced the ability to study cells from neutropenic patients,
the above noted differences in the cells being studied limit
the interpretation of the results.
The methods used in the detection of serum granulocyte
antibodies can be broadly categorized as those that detect the
surface antibody bound to the granulocyte and those that
detect the effects of the bound antibody, as shown in Table
1. Evaluation regarding the sensitivity of a particular test is
hampered by the fact that no single technique has been shown
to consistently detect all clinically relevant granulocyte an-
tibodies. Evaluation of specificity of a diagnostic test would
SHASTRI AND LOGUE
Table 1. Methods to Detect Antineutrophil Antibodies
Category Method
Detection of neutrophil surface Igs Radiolabeled
-Anti-lgG
-Protein A
-Anti-lgM
Intact staphylococci
Immunofluorescence
Flow cytometry
Enzyme-linked immunoassays
Detection of antibody effects Agglutination
Opsonization
Complement activation
-Antibodies to C3
-Cytotoxicity
Antibody-dependent cytotoxicity
require a disease condition that has a uniform etiology. The
heterogeneity and, at times, multifactorial etiology of sus-
pected immune neutropenic disorders makes such evaluation
difficult. Various methods and their comparisons have been
reviewed in detail by others64and what follows is a brief sum-
mary and comparison of various tests.
Methods to detect neutrophil surface-boundantibody. In
the more commonly used antineutrophil antibody assays,
heterologous granulocytes are incubated with serum or
plasma from patients and controls and the amount of neu-
trophil-binding antibody quantitated. It should be noted that
the presence of neutrophil alloantibodies may also give pos-
itive results in such indirect antineutrophil antibody tests.65
Neutrophil-binding immune complexes may also give posi-
tive results in tests used to detect neutrophil-bound Igs. The
pathophysiologicsignificance of such neutrophil-binding im-
mune complexes is described in the section on effector mech-
anisms of antineutrophil antibodies.
As outlined in Table I , several methods have been used
to quantitate Ig binding to granulocytes. In general, these
assays are comparable. Quantitative assays have the advantage
over qualitative assays such as the granulocyte immunoflu-
orescence test of not being subject to observer bias or expe-
rience. For all assays, the antibody-binding characteristics
and the antigen site density will contribute to the sensitivity
of the assay. Paraformaldehydefixation of granulocytesbefore
incubation with serum reduces the Fc receptor-mediated an-
tibody binding. Information regarding the impact of treat-
ment such as splenectomy or corticosteroids on antibody tests
is sparse and is referred to in the treatment section of this
review.
Radiolabeled antiglobulin antibodies or radio-iodinated
staphylococcal protein A (SPA) have been widely used by
several investigators to measure surface-bound antibodies on
sensitized target granulocytes.66-68Microscopic visualization
of intact staphylococci binding to sensitized, fixed granulo-
cytes on glass slides has also been used.@ The SPA binds to
Fc portions of IgG antibodies except IgG3. On comparison
of the results of SPA assay with the antiglobulin con-
sumption assay on sera from 42 patients with suspected im-
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
AUTOIMMUNE NEUTROPENIA
mune neutropenia, there was a remarkable correlation be-
tween the two methods, with the SPA assay being more
sensitive of the two.6' In that study, one patient with Felty's
syndrome had sequential samples drawn before and after
splenectomy. Presplenectomy antigranulocyte antibodies
were elevated, and over the ensuing 4 months there was a
reduction in these antibodies as measured by both assays.
The normalization of antibody corresponded to the recovery
from neutropenia. Lazar et a170 used reference sera of neu-
trophil specific antibodies and compared the antibodies de-
tected by SPA with the leukocyte agglutination and the gran-
ulocyte immunofluorescence tests. In this study, the SPA
assay was comparable to the other two assays and was slightly
more sensitive. Adsorption studies showed the granulocyte
specificity.
In the granulocyte immunofluorescence test (GIFT), Igs
bound to granulocytes are detected by a fluorescent dye-la-
beled antihuman Ig antib~dy.'~,~~ Damaged granulocytes are
autofluorescent; therefore, the assay requires considerable
observer experience. This test is positive with immune com-
plexes and is also qualitative.This assay also detects antibodies
against granulocyte-specific antigens. In patients with chronic
idiopathic neutropenia and neutropenia secondary to im-
munologic disorders, however, Van der Veen et a173found
only 15% positivity. These investigators found that serum
inhibitory activity to CFU-GM in tissue culture correlated
best with recurrent infection and myeloid hypoplasia.
With a principle similar to GIFT, the flow cytometric
analysis of granulocyte immunofluorescence can be used to
detect antibodies of any subclass directly on the patients'
neutrophils or indirectly on donor granulocytes after incu-
bation with patient sera. Cells other than granulocytes, such
as lymphocytes and monocytes, can also be tested simulta-
neously. Robinson et a174used flow cytometry to test the sera
of 92 patients with suspected autoimmune neutropenia.
Twenty-seven of the 92 patients demonstrated only IgG an-
tibodies, 4 had only IgM antibodies, and 7 had mixed IgM
and IgG antibodies, giving an overall 30% positivity. They
were able to detect antibodies against monocytes and lym-
phocytes in some patients.
Enzyme-linkedimmunosorbant assays (ELISA) using glu-
taraldehyde-fixed granulocyte-coated microtiter plates have
been reported. Sipos et a175tested sera from 38 patients with
progressive systemic sclerosis and found that 18.4% contained
antineutrophil antibodies. The results obtained with ELISA
concurred with results of granulocytotoxicity in that study.
On the other hand, Doughty et a176using a similar technique,
tested 54 patients with suspected immune neutropenia, and
found 44% positivity in both platelet and granulocyte ELISA.
The leukoagglutination test was positive in only 2% of patients
and lymphocyte cytotoxicity in 4%. Thus, antineutrophil an-
tibody ELISA using granulocyte-coatedplates does not seem
to be comparable to other methods of antibody detection. In
contrast, competitive inhibition ELISA using IgG-coated
plates is comparable to other methods used in our laboratory
(unpublished observations).
Methods to detect the effects of neutrophil-bound anti-
body. To detect the effects of granulocyte-bindingantibod-
1989
ies, live granulocytes are needed. This demands minimization
of contact of granulocytes with glass surfaces, excessive cen-
trifugal force, excessive temperatures, and manipulation.
The granulocyte agglutination test and its modification,
the granulocyte microagglutination assay, have been used
extensively to identify granulocyte-specific antigen^.^^^^' This
type of assay detects both IgG and IgM agglutinins and re-
quires active participation of granulocytes. In the first phase
of this test, the serum antibodies bind to the granulocytes
and "sensitize" them. The sensitized granulocytesthen move
toward each other and agglutinate. Both the sensitization
phase and the agglutination phase are time and temperature
dependent. This assay is sensitive and reliable, when per-
formed according to specified procedures. Lalazari et al"
studied 121 patients with autoimmune neutropenia of infancy
and could detect the antibody in 78.5% of patients. They did
not find a correlation between the severity of clinical mani-
festations, or the duration of disease with the strength of the
antibody titer. Circulating immune complexes, detected in
about half of patients tested (1 1 of 25), did not account for
the positivity of the test. In the same study, they found spec-
ificity for NA1 or NA2 antigens in 10% of their patients.
However, Ducos et a179found only 6 of 12 patients with this
disease to have antineutrophil antibodies detectable by mi-
croleukoagglutination. These investigators, as well as Jonsson
and BuchananB0in their study, did not find clinical differences
between antibody-positive and antibody-negative groups.
Both groups postulated that their findings may be due to lack
of sensitivity of the assays used. Sears et compared a
solid-phase radioimmunoassayfor serum granulocyte-binding
IgG to leukoagglutination in 32 patients with neutropenia of
various causes. All 15 patients with immune neutropenia
had elevated neutrophil-binding IgG, whereas only 10 were
positive by leukoagglutination. No patient with nonimmune
neutropenia was positive with either assay. In contrast, neu-
trophil binding IgG in non-neutropenic controls with rheu-
matoid arthritis was significantly higher than normal controls,
although not to the degree seen in patients with immune
neutropenia. None of the sera of patients with rheumatoid
arthritis without neutropenia was abnormal by leukoagglu-
tination. Thus, the leukoagglutination test was more specific,
although less sensitive than the granulocyte-bindingIgG assay.
In the ADLG," chromium-labeled granulocytes prein-
cubated with serum are lysed with release of chromium
when incubated with mononuclear effector cells. The in-
teraction occurs between the Fc receptors of the effector
cells and the antibody bound to granulocytes. This inter-
action is not dependent on the complement system and is
not influenced by immune complexes. While this test has
been successfully used for patients with Felty's syndrome,
adsorption of HLA antibodies is required. The optimal
effector cell to target ratio for the assay is 50: 1. The vari-
ability of effector cell activity among donors requires stan-
dardization of lymphocytes used in the test. The frequent
need for a large volume of lymphocytes from specified do-
nors and preparation of viable cells are limitations for the
routine use of this test.
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
1990
The opsonic activity induced by neutrophil binding Igs
has been detected by various methods. Boxer et all7 used
rabbit alveolar macrophages, which ingested sensitized human
neutrophils and reduced nitroblue tetrazolium dye (NBT).
The rate of NBT reduction was proportional to the rate of
neutrophil ingestion. The same group also used human gran-
ulocytes for ingestion of sensitized gran~locytes.~~ The acti-
vated oxidative metabolism of ingesting granulocytes was
measured by conversion of I4C glucose to carbon dioxide.
They found 53% concurrence between the opsonic activity
and increased granulocyte-bound Igs by flow cytometry.
Hadley et all6 measured antigranulocyte opsonic activity by
monocyte chemiluminensce and showed good correlation
with leukoagglutination and granulocyte immunofluores-
cence tests.
Complement activation induced by antineutrophil anti-
body has been measured by using monoclonal antibodies
against C3. Rustagi et a]*' studied complement-fixingability
of antineutrophil antibodies in the sera from 18 patients
with SLE, using radiolabeled monoclonal anti423 antibody.
Sera from patients with SLE bound greater amounts of IgG
to neutrophils than normal serum, but this IgG binding did
not correlate with the degree of neutropenia. In contrast,
serum samples from 10 neutropenic patients with SLE
bound significantly greater amounts of C3 to neutrophils
than sera from 8 non-neutropenic patients with SLE. Ad-
ditionally, a significant negative correlation was present be-
tween the neutrophil count and the C3-fixing ability of the
sera from SLE patients. When serum from patients with
SLE was separated by sephadex G-200 or Sephacryl S-300
gel filtration and selected undiluted fractions were tested,
C3 fixing ability appeared as a solitary peak in the mono-
meric IgG containing fractions, whereas neutrophil IgG-
binding activity was detectable in both the excluded and
included fractions. Separated normal serum did not fix C3
to neutrophils.
In the complement-dependent granulocyte cytotoxicity
assay, live granulocytes are incubated with serum and then
a nonhuman complement source is added.82283 The viability
of the cells is assessed by dye exclusion. Modifications of the
detection system, such as using double fluorochromatictech-
niques for staining viable and nonviable cells with different
colors, have been made." The pattern of reactivity obtained
with this assay is different from the agglutination assays, and
this assay also detects IgM antibodies.The clinical significance
of the antibodies detected by this technique has been ques-
tioned. McCullough et alg5used indium-labeled granulocytes
in patients with positive tests and failed to find any reduction
in half life or intravascular recovery of the labeled granulo-
cytes.
TREATMENT
The treatment of suspected immune neutropenia is de-
pendent on the underlying cause. Autoimmune neutropenia
of infancy, for example, is a disease in which spontaneous
remission is a rule and does not require specific aggressive
approach in most cases. In other immune neutropenic dis-
orders as well, the goal of therapy is prevention of recurrent
SHASTRI AND LOGUE
infections and not necessarily increasing the neutrophil
counts. Although the incidence of infection increases with
severity of neutropenia, infectionsare less frequent in immune
neutropenia than with corresponding degree of neutropenia
due to other causes. On the other hand, qualitative defects
in neutrophils due to antineutrophilantibody may predispose
a patient to infections despite having normal neutrophil
counts.
As with other autoimmune blood disorders, splenectomy
has often been used in the treatment of immune neutropenia.
The rationale for its use includes eliminating antibody, com-
plement, and immune complex-mediated neutrophil de-
struction by splenic reticuloendothelialcells, and eliminating
splenic production of antineutrophilantibody or T-suppressor
activity. Its use for treatment of Felty's syndrome dates from
1932, when Hanrahan and MilleP6 first described splenec-
tomy for this syndrome. Immediate response to splenectomy
with an increase in neutrophil count occurs in 80%to 90%
of ca~es.'~ However, neutropenia recurs in 20% to 30% of
cases.'' In one study, the response to splenectomy was pre-
dicted by high levels of serum neutrophil binding IgC pre-
operatively, but not with spleen size.89In that study, thera-
peutically successful splenectomy was also accompanied by
a reduction in serum neutrophil-binding IgG. The failure of
splenectomy in some cases may be due to the presence of
antibody-dependent lymphocyte-mediated granulocytotox-
icity.gORecurrent infections despite normalization of neu-
trophil counts occur in approximately one-third of the pa-
tient~.'~ The reason for this may be the qualitative defects in
neutrophil function described elsewhere in this review. In a
literature review of 63 reports of 265 splenectomies for this
disease," the postoperative mortality was 4.2%. Because of
the risks associated with this procedure, splenectomy in Felty's
syndrome patients should be reserved for those with profound
neutropenia accompanied by recurrent infections or con-
current immune hemolytic anemia. It should not be used as
a prophylactic measure against serious infections. The role
of splenectomy in other diseases with immune neutropenia
is ill defined. Loughran et a19' reported results of splenectomy
in four patients with large granular lymphocyteleukemia who
had severe neutropenia with recurrent infections. Initial im-
provement in neutrophil counts was seen in all the patients,
but this increment was sustained in only two patients. Both
of the nonresponding patients had no change in the levels of
neutrophil-reactive IgG, whereas in the one patient tested
among the two that responded to splenectomy, there was a
decrease in the antibody titer. The responding patients also
benefitted clinically by dramatic reduction in the frequency
of infections. Splenectomy did not have any effect on the
underlying lymphoproliferative disorder. Newland et al?* on
the other hand, did not see any response to splenectomy in
their four neutropenic patients with this disease. All of their
patients who underwent splenectomy, including three with
normal neutrophil counts, showed significant lymphocytosis
postoperatively and an increment in bone marrow infiltration
with lymphocytes. There is minimal experience for splenec-
tomy in immune neutropenia associated with SLE, because
treatment is generally not required for neutropenia, and cor-
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
AUTOIMMUNE NEUTROPENIA
ticosteroids are more effective. In a review of splenectomy
in SLE, a patient with severe neutropenia and recurrent bac-
terial infections obtained lasting benefit after ~plenectomy?~
Corticosteroidshave been used to treat autoimmune blood
diseases, including autoimmune neutropenia. Potential
mechanisms of action include reticuloendothelial blockade
and decreased antibody production. The latter may be the
result of its effect on T-cell function. Cines et a166noted that
systemic corticosteroids produced an increase in circulating
neutrophil counts with an associated decrease in antineutro-
phi1 IgG in four patients with immune neutropenia. Systemic
corticosteroids have not produced a desirable response in
patients with Felty's syndrome94and T-y lymphocyt~sis:~
and may increase the rate of infections. In contrast, corti-
costeroids are beneficial for some patients with chronic id-
iopathic n e ~ t r o p e n i aand
~ ~ SLEy6 whenever treatment of
neutropenia is warranted in these diseases. Corticosteroids
have also been used to treat antibody positive immune neu-
tropenia in Hodgkin's disease?' Corticosteroid therapy pro-
duced a correction of neutrophil counts with a reduction in
antineutrophil antibodies.
Intravenous (IV) Igs have been used with anecdotal reports
of success in children and adults with immune neutrope-
nia.98-102 Although long-lasting responses have been reported
in two patients with autoimmune neutropenia of infancy,lW
the responses have generally been short lived, lasting for about
2 weeks; however, the short response has allowed successful
treatment of infections in these patients. This type of success
has not been achieved in patients with Felty's syndrome.
Breedveld et allo3used highdose intravenousgamma-globulin
to treat neutropenia of five patients with Felty's syndrome
and did not observe any change in neutrophil counts. As
with autoimmune hemolytic anemia, the required IV Ig doses
may be significantly higher than those for immune throm-
bocytopenic purpura.'" The precise mechanism of the effect
of IV Ig is not clear, but among the explanations that have
been put forward include the transitory reticuloendothelial
blockade,Io4and the possible anti-idiotype suppression of au-
toantibodie~.~~~
Hematopoietic growth factors can support the proliferation
and terminal differentiation of myeloid progenitor cells.'o6
Additionally, they enhance granulocyte functions such as
phagocytosis, chemotaxis, and antibody-dependent cell-me-
diated c y t o t o x i ~ i t y .Molecular
' ~ ~ ~ ~ ~ ~cloning and expression
of recombinant human granulocyte-macrophage colony-
stimulating factor (GM-CSF)'w and granulocyte colony-
stimulating factor (G-CSF)' l o has allowed evaluation of their
clinical benefit in a variety of situations involving bone mar-
row failure, such as in patients with the acquired immuno-
deficiencysyndrome (AIDS), aplastic anemia, cyclic neutro-
penia, and the myelodysplastic syndromes.L1'~LL2 They also
shortened the duration of neutropenia in patients treated with
cytostatic chemotherapy, or total body radiation in patients
receiving autologousbone marrow transplant." I Whereas the
use of growth factors in the treatment of autoimmune neu-
tropenia is largely in forms of anecdotal case reports, the
initial reports seem encouraging. In view of the short-term
response in reported cases, these treatment modalities are
1991
most useful in patients with active systemic infection or those
undergoing major surgery. Gasner et a l l i 3 treated four patients
with severe chronic neutropenia (2 with chronic idiopathic
neutropenia, 1 with congenital neutropenia, and 1 with au-
toimmune neutropenia) with rhGM-CSF. The absolute neu-
trophil count increased in all four patients, from less than
0.25 X lo9to 3.2 to 19.2 X 109/L within 2 weeks ofbeginning
rhGM-CSF therapy. Two patients had life-threateninginfec-
tions that resolved during therapy. The other two had major
ano-rectal surgery during rhGM-CSF treatment and had no
postoperativeinfections. Takahashi et reported successful
use of G-CSF in a 57-year-old patient with granulocyte an-
tibody-positive autoimmune neutropenia. We have success-
fully treated a patient with positive antineutrophil antibody
with G-CSF. This patient had a 20 year history of severe
neutropenia associated with pyoderma gangrenosum. He
underwent surgery for a gangrenous gall bladder and was
successfully treated with daily G-CSF at a dose of 2 pg/kg.
His absolute neutrophil count increased from below 0.5 X
109/L to greater than 5 X 109/L during more than 3 months
of treatment with G-CSF.
The experience with the colony-stimulating factors in pa-
tients with Felty's syndrome, although in case reports form,
is likewise encouraging. In one report, the patient had a
prompt increase in neutrophils after 6 days of GM-CSF.
However, the patient had a flare of arthritis concomitant with
the neutrophil re~ponse.''~ However, in two other reports,
there was improvement in neutrophil counts with GM-CSF
treatment without a flare in arthritis.'L6sIL7 In a reported case
in which both G-CSF and GM-CSF were used 1 year apart
in a patient with Felty's syndrome, G-CSF produced a more
rapid response, whereas GM-CSF produced a longer-lasting
response."' These investigatorsrecommended G-CSF for life-
threatening infections in patients with Felty's syndrome be-
cause of the prompt response. Whereas there are reports of
both success and failure of GM-CSF in T-y lymphoprolif-
erative disorder,lL9-'22
there are at least three reports of short-
term neutrophil increments with G-CSF in this condi-
tion~121,123,124
Other treatment modalities have been used occasionally
to treat immune neutropenia. Treatment of the systemic dis-
ease of rheumatoid arthritis with parenteral gold therapylZ5
or D-penicillamine'26may be beneficial in associated Felty's
syndrome. Cytotoxic agents have also been used to treat an-
tibody-positive immune neutropenia. Methotrexate therapy
decreased neutrophil-reactive IgG, while increasing neutro-
phil counts within 1 to 2 months of starting therapy in four
patients with Felty's syndrome.lZ7Plasmapheresis has also
been used with success in Felty's syndromei2*and chronic
. ~ ~ are also case reports of suc-
idiopathic n e ~ t r o p e n i aThere
cessful use of cyclosporin in Felty's syndrome129and T-y
lymphocyto~is.'~~ Lithium carbonate treatment generated
considerable initial interest. However, responses to lithium
carbonate, when judged by doubling of neutrophil counts in
patients with less than 0.5 X lo9 neutrophils/L, occur in less
than one-fourth of patients and its beneficial effect in pre-
venting infections in responding patients is q~estionable.'~'
Lithium therapy is not without side effects and there is a
 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.
1992
suggestion that patients with Felty’s syndrome may be more
susceptible to adverse effects of 1 i t h i ~ m . I ~ ~
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 From www.bloodjournal.org by guest on January 4, 2018. For personal use only.

1993 81: 1984-1995

Autoimmune neutropenia [see comments]

KA Shastri and GL Logue

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