Normal Host Defense and Primary Immunodeficiency

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					Normal Host Defense and Primary Immunodeficiency

                    Janet Wong, M.D.

Functions of the Vertebrate Immune System                               Our immune systems need to be able to discriminate between self and
                                                                        foreign in a way that allows it to exclude, eliminate or kill the foreign
                                                                        invader. Any deficits in these functions will result in either an increased
                                                                        frequency or severity of infections, that essentially produce disease in
€   Discriminate between self and foreign
                                                                        otherwise healthy individuals. If the organism is able to get past the native
€   Exclude, eliminate or kill foreign invasion                         immune, and the native immune first exists in the absence of previous

€   Develop memory and amplified recall response                        exposure to the organism. Infection can occur, but the disease will not
                                                                        occur because the immune system suppresses the growth prior to that.
€   Deficits result in
                                                                        Disease occurs if the tempo of replication is faster, but yet allows the
    •    Increased frequency or severity of infections with pathogens   immune system to catch up, and then severe fatal infection occurs in a
    •    Infections with nonpathogenic, opportunistic organisms         situation where the organism is able to replicate more rapidly than the
                                                                        immune response. And of course this can happen in one of two ways;
                                                                        either the organism is very rapidly growing, or the immune system is slow
                                                                        in responding, and of course if you have an inadequate immune system.

Components of Innate (Preexisting) Immunity
                                                                    And our phagocytes, which of course we routinely end up knocking these
                                                                    out in cancer chemotherapy and other sorts of interventions that are being
€   Barriers - skin and mucus membranes, normal flora, spleen
                                                                    performed in trying to help patients. So the phagocytic cells included of
€   Opsonins - complement, collectins, CRP                          course are neutrophils and monocytes in the blood, active follicles in the

€   Phagocytes - neutrophils, monocytes, macrophages and NK cells   tissues. These cells of course regularly protect us initially from viruses,
                                                                    primarily in the absence of prior increase in the antigens specific immunity.

                                                                    What are the components of antigens specific immunity? While these are
                                                                    becoming the illustrated test to find HIV, The C4 T-cells are particularly
                                                                    important because they are sort of the regulators of everything else. They
                                                                    set the tempo for the whole immune response, that of rest of the antigens
                                                                    specific system. They do it by secreting proteins called cytokines. In
                                                                    addition to secreting cytokines, they have proteins that are expressed on the
                                                                    membrane when they are activated by a form of antigen, and these proteins
                                                                    help enhance the recognition phase of the immune response, by including
                                                                    antigen presenting subfunction, and also act on B cells. And finally there
                                                                    are B cells and antibodies of course that protect us from bacterial
                                                                    pathogens, especially capsular pathogens, but in addition, play an
                                                                    important role in protecting us against a wide variety of things, such as viral
                                                                    infections and so forth.

                                                                    The patient presents to you with a clinical problem, usually infection,
                                                                    sometimes odd immunity, sometimes malignancy, and you must try to
                                                                    figure out what is going on. So, your looking at infections that are associ-
                                                                    ated with or patients that present with recurring or persistent sign of
                                                                    pulmonary or ear infections, I usually like to break them down into two
                                                                    groups. If they occur without GI infections, the most common deficits are
                                                                    deficits in innate respiratory mucosal defenses. Allergies were secondarily
                                                                    affects of the defenses, or deficits in humoral immunity, that is antibody
                                                                    production in particular. If there are also GI type of infections, than antibody
                                                                    deficiencies becomes even the more vital. So what are the components of
                                                                    the innate defenses that are intrinsic to our respiratory tract. We do not get
                                                                    many humans that have this deficiency. And then finally, macrophages in
                                                                    the lung, and those play a primary role in clearing microbes in the first
                                                                    patch effect, and also in secreting cytokines that were recruited for other
                                                                    intentions. Well the most common one I will refer to is unfavorable
                                                                    anatomy. Occurring in the first year or two of life. In other situations,
                                                                    secondary to infection, or other anatomical abnormalities such as we seen
                                                                    in individuals with cleft palate and lip, you may have difficulty with normal
                                                                    cleft, because of unfavorable anatomy. And then of course there are
                                                                    secondary or primary cellular dysfunction. Secondary being overwhelmingly
                                                                    the more common, and usually being secondary to prior infections. So the
                                                                    ciliated cells don’t function normally. That is commonly associated with
                                                                    cystic fibrosis. So that is a rare immune deficiency localized in the
                                                                    respiratory tree, that is usually on the bottom of our evaluation list.

                                                                    So how does one go about evaluating these children who have recurrent
                                                                    infections in the sinus and ears. After you take the history, evaluate the
                                                                    patient, and do a radiograph of the sinuses and of the chest, looking for
                                                                    abnormalities. Screening allergy evaluation generally to those, the second
                                                                    part of that is a good history and family history. Swab tests of course is
                                                                    straightforward, easy, and a part of the evaluation. Ancillary evaluation may
                                                                    occur except in those cases where we have exhausted other possibilities,
                                                                    and this means obtaining ciliated cells from the nose, or the bronchial tree.
                                                                    The problem here is you have to get it from a noninflamed area, because

    Components of Antigen-specific Immunity         otherwise you will be looking at the secondary abnormality.

                                                    Humoral immunity. This is most likely to be a problem in individuals who
                                                    have recurrent respiratory tract infections, particularly associated with GI
€    CD4 T cells (helper/master control)
                                                    tract infections. There are four basic classes of antibody: M, G, A and E. In
€    Cytokines -IL-2, IFN-( TNF-a/IL-4, IL-5        antibody G there are four subclasses. It is in your primary response to

€    Cognate help for APC/B cells via CD40 ligand   immunization, typically produce predominantly IgM, and subsequently one
                                                    switches to making IgG and/or IgA. The basis of that switch is distributed
€    CD8 and 75 T Cells
                                                    by T-cells, but the essence of that observation is that if one had the deficit
     •   Cytotoxicity                               of T-cell function, one will have the deficit in the antibody production,
     •   Cytokines                                  because of the problem of switching from IgM to IgG, and of making high-
                                                    dependent antibodies which are also dependable. The major mucosal
€    B cells and antibody
                                                    humoral defenses are the secretory IgA. There are two subclasses, the only
                                                    thing we’re doing about that, is that the secretions that are approximately
                                                    a quarter of analysis of two subclasses as opposed to one, is almost all IgA
                                                    1. So it’s useful to have it in the secretion since it is more likely to remain
                                                    intact than those organisms around. IgA is absent from the secretions at
                                                    birth, it appears about a month at life and reaches out about six to eight
                                                    years of life. So again the baby is born without good mucosal senses. And
                                                    probably we’re saying here that IgA deficiency is almost always detectable
                                                    in the blood. There are extremely rare cases where the deficit is only
                                                    manifested in the secretions. But for all intents and purposes, one needn’t
                                                    collect secretions to evaluate the patient for IG deficiencies, one can check
                                                    it out in the blood.

Recurrent/Persistent Sinopulmonary and Ear
                            Infections                                     When to suspect primary immunoglobulin or antibody deficiency. Well, it’s
                                                                           when ear and sinus infections are more common than in the general
                                                                           population, and without other explanation. Especially if associated with
€   Without GI Infections
                                                                           recurrent pneumonias. Of course if you have GI infections or viral patho-
    •   Suspect deficit in innate, respiratory mucosal defenses, allergy   gens, that should raise your level of concern for an underlying humoral

        or humoral immunity                                                immune deficiency. I have listed some data here from a report a few years
                                                                           back on the frequency of otitis, and so forth, and as you all know it is
€   With GI Infections
                                                                           extremely common. So otitis would not raise a big red flag. If it appeared in
    •   Suspect antibody deficiency                                        other things, one may need to find suspicious, and begin to evaluate for
                                                                           humoral immune deficiency, which we will talk about in a moment.

   Intrinsic Defenses of the Respiratory Mu-
                                cosa/Lung               So what are the danger in immunodeficiencies associated with a primary
                                                        deficit in the antibody production? Well there are two major X-linked
                                                        immune      deficiencies.      X-linked     agammaglobulinemia,            or
                                                        hypogammaglobulinemia, and the X-linked hyper IgM syndrome. These
€ Normal Epithelial Structure/Function
                                                        conditions almost always present within the first two years of life, but like
   •   Mucociliary clearance                            all humoral immune deficiency, rarely presents before four to six months of

   •   Antimicrobial activity                           life, because of the presence of maternal antibodies, subserving the
                                                        function that the wholesome antibody would ordinarily survive. So again,
       1.   Pro/Anti inflammatory Cytokine Production
                                                        under six months of age, it is unlikely, it is usually by three or four months
       2.   Opsonins - surfactant apoprotein A          of age that you might have problems in immune deficiencies. Common

   •   Alveolar Macrophages                             variable immune deficiency remains such at all. It is common heteroge-
                                                        neous, and is onset earlier. About half the patients present first in
       1.   Antimicrobial activity
                                                        adulthood, and it is the most common immunodeficiency. IgA deficiency
       2.   Pro/Anti Inflammatory/Cytokine Production   occurs in one in about 700 individuals, but most are wholly asymptomatic.
                                                        Most of them do not report problems more frequently than the general
                                                        population. There are a subset of individuals who have IgA deficiencies,
                                                        that do have problems. And finally there is a condition referred to as
                                                        transient hypogammaglobulinemia of infancy, which is recently frequent
                                                        and mimics the most closely common variable.

       Problems with Normal Upper and Lower
       Respiratory Tract Barriers to Infection

€ Unfavorable Anatomy
€ Abnormal mucus transport or rheology
   •    Cystic Fibrosis
   •    Secondary or Primary Ciliary Dysfunction
€ Allergy

 Evaluation for Deficits in Respiratory Barri-
                                 ers                                      So the laboratory evaluation for primary humoral immunodeficiency should
                                                                          include initially simply 5 hemiummuoglobulins in the blood, I, V, G, M & A.
                                                                          One can also utilize information based on the majority of the individuals that
                                                                          makes specific antibodies. There are two classes that you can easily get
€ History, Physical, Radiographic
                                                                          information about. One is the natural antibodies that we make and set off
€ Screening Allergy Evaluation                                            as red cells, which is called hemagglutination. These appear toward the

€ Sweat Test                                                              end of the first year of life and accumulate after that. The other is to
                                                                          measure how many antibodies the patient has made to the routine travel
€ ENT Evaluation
                                                                          immunization that he or she has perceived. Will give you some measure
€ Ciliary Evaluation - in most refractory cases after exclusion of more   whether that individual can make antibodies. Remember if you are doing
   common diagnoses                                                       these tests too early, like at six months of age, most of the antibodies can
                                                                          be marked, but at a year later, most of these can be able to get some sense
                                                                          at whether the child can make specific antibodies. This along with
                                                                          immunoglobulins provides a good initial screening, and if they are normal
                                                                          one will generally end up just waiting and evaluating further, only if
                                                                          problems are more severe. And then those secondary evaluations would
                                                                          include the following. Furthermore, looking at one individual to make
                                                                          antibodies to saccharides will tell you something you can not get from
                                                                          looking at antibodies response. There are individuals who have a particular
                                                                          problem making antibodies with polysaccharides. The problem with that of
                                                                          course, is that we normally do not expect children under two years of age
                                                                          to make antibodies of polysaccharide to any great efficiency whatsoever. So
                                                                          the test is fully useless under that age. And it is problematic to interpret off
                                                                          before four or five years of age, because during that period of time, the
                                                                          response is suboptimal, although it does occur. Also during IgG subclasses
                                                                          may be inducing some patients.


€ Four major classes - IgM, IgG, IgA and IgE
€ Four subclasses of IgG - and two subclasses of IgA
€ Antibody bound to microbes can neutralize (virus), activate complement
   and/or bind to specific receptors on phagocytes for IgG, IgA or IgE
€ Primary Ab response - Predominantly IgM
€ Secondary Ab - enhanced recall response, switch to IgG (IgA), largely
   T cell dependent

 Age-related Changes in Immunoglobulin             So, the thing that is always important to know is that things change with

                Concentrations                     age. You need to make sure that your laboratories report the values that
                                                   you’ve asked to, with a proper gauge related norm. Because if they are not,
                                                   they are often going to look low, when they are perfectly fine to the child.
                                                   The important thing to note then, is when your looking at IgG, there is a
   Age         IgG-mg/dl   IgM-mg/dl   IgA-mg/dl   physiologic manner that occurs in about 4-6 months of age, that on
                                                   average, goes down to about 400 or so, and then rises thereafter. But it is
               (% adult)   (% adult)   (% adult)
                                                   not definite that this child has an underlying immune deficiency. So you
  Neonate      1031 (89)    11 (11)      2 (1)     need to think of the values given in the context of age, and whether this
                                                   child was full term or not. Again norms for age are important.
 4-6 months    427 (37)     43 (43)     28 (14)

7-12 months    661 (58)     54 (55)     37 (19)

25-36 months   892 (77)     61 (62)     71 (36)

 6-8 years     923 (80)     65 (66)    124 (62)

   Adult         1158         99         200

                    Secretory Immunity

€   Mucosal associated lymphoid tissues contain T and B lymphocytes
€   Secretory IgA - two IgA molecules linked to an epithelial derived
    secretory component
€   IgA is absent from mucosal secretions at birth and reaches adult
    concentrations at 6-8 years of age

    When to Suspect Primary Ig or Antibody
                     Immunodeficiency                                        So what are the diagnostic criteria by which we establish the diagnosis
                                                                             from one another is immune deficiencies.

€   Ear and sinus infections more common than in the normal general
    population; recurrent/refractory pneumonia or GI infections with viral
    pathogens or Giardia are indicative of an antibody immunodeficiency.
€   Normal frequency

      Age               URTI               Otitis           Diarrhea

    <1 year              6-7              1 (0-6)             1-2

    1-2 years             8               1(0-6)                2

    3-6 years            6-8             <1 (0-6)               2

    Major Immunodeficiencies with a Primary
            Deficit in Antibody Production

€   X-linked agammaglobulinemia and X-linked hyper-lgM syndrome -
    onset of recurrent infections usually between 6-24 months of age
€   Common variable immunodeficiency - onset variable - may
    present in adulthood
€   IgA deficiency - most common (1:700) often asymptomatic
€   Transient hypogammaglobulinemia of infancy

 Laboratory Evaluation of Presumed Primary
              Humoral Immunodeficiency

€ Initial - IgG, IgM and IgA, isoagglutinins and/or antibody to previous
   vaccines -diphtheria, tetanus
€ Secondary evaluation if indicated
   •   Production of antibody in response to booster diptheria/tetanus and
       pneumococcal     vaccine    (non-conjugated);     assessment     of
       polysaccharide response unreliable at <2yr, difficult <5yr
   •   IgG subclasses
   •   Analysis of B cell number, T cell number end function in vitro

  Diagnostic Criteria in Primary Humoral Im-                                X-linked agammaglobulinemia tells you right there that you should not
                                                                            suspect any much in her.


€ X-linked agammaglobulinemia, markedly reduced
  •   All Ig classes, particularly IgG -Production of specific antibodies
  •   Numbers of B cells
  •   Normal number and function of T cells

  Diagnostic Criteria in Primary Humoral Im-
                       munodeficiency                                        You do see it in boys of course, and what one sees is fairly straightforward.
                                                                             All immunoglobulin classes are markedly reduced, if not absent. IgG in
                                                                             particular, being low, would never again in the first few months of life will
                                                                             have an internal IG that may make it more difficult to interpret. They do not
€ X-linked hyperlgM syndrome
                                                                             make specific antibodies, or make very little to immunize them. And this
   •   Clinical features similar to X-linked agammaglobulinemia plus         disorder is characterized by the absence of new lymphocytes. T-cells are

       increased risk for Pneumocystis, Cryptosporidium, neutropenia and     completely normal. Now, the X-linked hyper IgM syndrome, these individu-
                                                                             als present very much like X-linked agammaglobululinemia, but with some
                                                                             additional features. So, they don’t make much IgG or any antibodies, but
   •   Markedly reduced IgG, IgA                                             make plenty of IgM. The name hyper IgM syndrome refers to the fact, that
   •   High or Normal IgM                                                    the amount of IgM that they have is normal or is elevated by the appearance
                                                                             of the G or A they have. They can not switch immunoglobulin plasma today,
   •   Normal numbers of B and T cells
                                                                             every response they make looks like a primary. They make IgM, they make
   •   Defect in CD40 ligand expression                                      IgM look like IgM. They do not do this, they do not get IgM, they do not have
€ Common variable immunodeficiency                                           a recall. They have markedly reduced G and A, higher than normal IgM,

   •   IgG concentrations reduced by >50%, usually IgA and IgM also          normal numbers of B and T-cells and they have a defect in the protein.

                                                                             Common variable immune deficiencies. The most common finding here is
   •   Antibody responses to all classes of antigens diminished              that the IgG concentration is reduced by more than 50%, commonly being
   •   B cells present, usually in normal numbers; T cell numbers and        less in an adult in a 200-300 mm per liter that is more than the 50% below
                                                                             the two standards used. IgA and IgM may also be reduced to that various
       function variable
                                                                             form. Their ability to make specific antibodies is apparent. The response
   •   Allergy, autoimmunity, malignancy may occur                           to all classes of antigens that are proteins and polysaccharides are
€ IgA Deficiency                                                             diminished. These cells are present and are usually there in normal
                                                                             numbers, but not always. T-cell number and function varies. Some of these
   •   lgA <5 mg/dl
                                                                             patients have T-cell function defects. In addition to the types of infections
   •   May occur in kindreds with common variable immunodeficiency or
                                                                             that I have mentioned, they commonly engulf a lot of immune diseases, and
       co-exist with IgG subclass deficiency; allergy/autoimmunity may co-   malignancy may also develop. In fact, overall malignancy increases in

       exist                                                                 patients with immune deficiencies.

€ Deficiency of one or more of the IgG subclasses (IgG 1, 2, 3, 4)
                                                                             IgA deficiency. By that I mean an IgA that is undetectable. There are a
   •   Significant if specific antibody production is low                    bunch of patients out there with IgA that are floating around, at about 50-
   •   IgG2, G4 - capsulated bacteria                                        75% of what is called a lower limit than normal. Those individuals identifies
                                                                             another problem in antibody production, should not have difficulty with
   •   IgG3 - recurrent respiratory infections
                                                                             infections. A true IG deficient person is less than five. It may occur in
   •   caveats - values should be markedly reduced; difficult <2-4 yr due    hindrance, in association with common vertical and immunodeficiencies or
       to low range of normals                                               coexist with IgD subclasses. When it does, it is more likely to be associated

   •   may occur in association with IgA deficiency                          with a problem of recurring infection. Recall that I said that 1 in 700
                                                                             individuals that is probably someone in this room that is IG deficient, and
                                                                             yet, does not have any problems. It is significant if specific antibody
                                                                             production is low. Remember, we have four IgD subclasses. The usual
                                                                             definition of lower than normal is that they fall below the fifth percentile. By
                                                                             definition if you do four tests, you have 4/5% of an opportunity to find an
                                                                             abnormality. That is 20% of the time just by statistical normals, you do an
                                                                             IgD set of subclasses, you are going to find one of them well. Don’t interpret
                                                                             that as being abnormal. What one sees in individuals who have deficits in
                                                                             G2 or G4, is definite cause of recurrent effects to the capsulated bacteria,
                                                                             pneumococcus. Patients with IgG 3 deficiencies, commonly have a
                                                                             recurrent respiratory infections, and lower respiratory tract infections. It is
                                                                             very difficult when interpreting these under about 2-4 year of age, because
                                                                             the value with set for IgD 1 are commonly so low, it is difficult to interpret.
                                                                             Particularly IgD 4, even in an adult is the lower one than normal that
                                                                             overlaps the level of delectability. So G4 deficiencies are almost undefin-
                                                                             able. So these tests are worth doing only on a patient who you have not
                                                                             found a deficit in total G and A, are were thinking of the context of looking

  Transient Hypogammaglobulinemia of In-                                   for specific antibody production.

                                fancy                                      Finally transient hypogammaglobulinemia of infancy. What this appears to
                                                                           represent    is   simply    an   attenuated     or   prolonged     physiologic
                                                                           hypogammaglobulinemia. You will recall the normal values fall in the
                                                                           neighborhood of about four months of age, and if that is attenuated or
€ Accentuated and prolonged physiological hypogammaglobulinemia
                                                                           prolonged, then there will be a deficit in IgG beyond the first six months out
  (Ig(G predominantly)                                                     to 12-18-24 months of life. It is normal. But what you see in these

  •   Normal event in very low birth weight prematures                     individuals, is that IgG values increase with time. Specific antibody
                                                                           responses are intact. That is if you are concerned and anxious, you can
  •   Ig increases with time, specific antibody responses are intact
                                                                           look at whether the individual is making antibody immunizations that he or
      (quantity may be slightly low), B cell and T cell numbers/function   she has been given. The magnitude of that response may be somewhat
      normal                                                               lower than in an otherwise normal child, but they do respond. B and T-cell
                                                                           numbers in function are normal. This may be difficult to differentiate initially
  •   May be difficult to differentiate initially from CVID
                                                                           from common variables. The common variables does not lock in percent
                                                                           at a year of age. So if you see sort of a mixed picture with someone with a
                                                                           low G, and relatively normal, slightly low A. A common variable is most
                                                                           likely to be the case. You can evaluate the patient in one of two ways. You
                                                                           can simply follow the patient, repeating the immunoglobulin values in a
                                                                           matter of two months, depending on how the patient is doing, and how
                                                                           anxious they are. Or you can look for production of specific antibodies as
                                                                           I mentioned to see how well they are doing. Either study is reasonable, and
                                                                           treatment of infections, treatment may begin.
                                                                           So what about frequent humoral immune deficiency, I would think transient
                                                                           hypergammaglobulinemia. Well the only real therapy that we have that is
                                                                           specific is regular adhesions of intravenous immunoglobulin. That is
                                                                           indicated in individuals with proved primary immune deficiency in which
                                                                           they have no IgG, and/or deficits in specific antibody production, or maybe
                                                                           indicated in secondary immunodeficiencies associated with diminished
                                                                           specific antibody production. It is generally contraindicated in an isolated
                                                                           IgA deficiency. The most common of course is allergies. Patients with
                                                                           asthma commonly have the elevated IgGs. What I’m talking about are not
                                                                           just to put modestly IgG’s’s. I’m talking about also very high IgGs. The most
                                                                           common one that you heard about is called the hyper IgE syndrome. Those
                                                                           individuals present as if they had a neutrophil or optimum defect, which I
                                                                           will talk about next. And chronic or recurrent staphylococcal infections of
                                                                           the skin and gram-negative staphylococcal and fungal infections of the
                                                                           lungs, commonly engulfed in cavities in the lungs. They have a skin rash
                                                                           that looks somewhat different than you have seen. The Wiskott-Aldrich
                                                                           syndrome is another form of combined immune deficiency. It presents with
                                                                           high values of IgG. The hallmark of this disorder is thrombocytopenia, and
                                                                           it is the most penetrated form of leukemia. These patients presented with
                                                                           thrombocytopenia uncover definite eczema and thrombocytopenia is
                                                                           characteristic in that the platelets are small. It is about the only
                                                                           thrombocytopenia where the platelets are small.

   Treatment of Humoral Immunodeficiency
                                                                           Unusual or unusually severe invasive infections with bacterial pathogens,
                                                                           or opportunistic bacteria, organisms that would not ordinarily produce in
€ Regular Infusions of IGIV
                                                                           healthy individuals. In those individuals you can expect to find a definite
   •   Proved primary immunodeficiency with low IgG and/or deficits in     either in one of their barriers, and the common one being burns, or

       specific antibody production                                        deficiencies such as in diabetes. As you can probably guess, the outer
                                                                           hand and both feet look like this as well. Anyone want to tell me what this
   •   Secondary immunodeficiency associated with diminished specific
                                                                           is? So, the spleen is a good thing to have around. It is a filter. It is the most
       anybody production - CLL, pediatric AIDS, bone marrow transplants   efficient organ at removing non-antibody coated, complement opsonized
€ Contraindicated                                                          bacteria. So if you are a person who does not have preexisting immunity to
                                                                           that bug, now all you got is complement and things like CRP, you want your
   •   Isolated IgA deficiency
                                                                           spleen, because the spleen has a lot of macrophages in it, and that
                                                                           organism is best at kicking out those cells that only have complement on
                                                                           their to opsonize it. It is also a sight of antibody production. What about
                                                                           opsonins? There are a whole bunch of copper proteins.
                                                                           2). They move about three things: they converge at C3 in the middle, and
                                                                           C3 does several things; if it is down to the surface of the particle it is
                                                                           upside, when it is down, it is prereleasing a particle called C38 which is
                                                                           chemotactic, which helps tract neutrophils, and it also then plays a role in
                                                                           acting other common components forward down to the right and below,
                                                                           which went down to the plasma membrane of certain organisms. So they
                                                                           move from left to right beginning with C1, converging in C3, an alternative
                                                                           pathway enters there as well. Again, converting on C3 is the key feature.
                                                                           Now the only other thing to remember about this whole pathway, is with 2
                                                                           laboratory tests, you can access the whole thing. You can screen your
                                                                           patient with those 2 tests, and that is really all you need to know. So there
                                                                           are two major types of problems the patients with complement dysfunction
                                                                           present with is infections and one is not infections. The most common one
                                                                           that you will see is a patient with recurrent invasive infections. About 5% of
                                                                           the patients present with meningococcal infections for the first time,
                                                                           actually have a copper disorder. The treatments will be greater than that if
                                                                           the infection is unusual in type. So the frequency may go up to 10 or 15%
                                                                           in those groups, whereas if you are looking at a young child with a B, it is
                                                                           going to be less than 5%.

       Syndromes Associated with Excess IgE

€ Modest elevations - atopy
€ Marked elevations - Generally >1000 IU
   •   Hyper Ig E syndrome - chronic/recurrent Staphylococcal >gram-
       negative and fungal infections of skin, lungs
   •   Omenns syndrome, Wiskott Aldrich syndrome - forms of combined

Unusual or Unusually Severe Invasive Infec-
 tions with Bacterial Pathogens or Opportu-
                  nistic Bacterial Fungi

€ Deficits in Cutaneous Barrier
   •   Burns
   •   Vascular insufficiency
€ Deficits in Systemic Innate Defenses
   •   Spleen
   •   Complement
   •   Phagocytes

                      Splenic Function

€ Filter - most efficient at removing non-antibody opsonized bacteria
€ A site of antibody production
€ Splenic absence/dysfunction predispose to overwhelming infection with
   capsulated bacterial pathogens, particularly S pneumoniae


€ Proteins that when bound to the surface of cells enhance their ingestion
   by phagocytes
€ Primitive opsonins - acute phase reactants
   •   Mannose binding protein (MBP)
   •   C-reactive protein (CRP); opsonin for pneumococci
   •   Others. e.g., fibronectin
€ Complement
€ Antibody


€ Complement activation is initiated through
   •   A cascade of proteins and regulated proteases
       1.   Classical pathway activated by IgG, IgM. CRP, MBP bound
            to a microbe
       2.   Alternative pathway fluid phase activation amplified on microbe
   •   Activated complement -opsonic (C3b). chemotactic (CSa) and lytic
   •   Alternative >classical pathway activity diminished in neonates (50-
       75% adult)

                   Complement Deficiency

€ Recurrent invasive infections with Neisseria meningitidis) or N gonorrhea
   •   5% initial overall, greater with unusual type or older age, -30%
       recurrent have defects
   •   Any component except C1, particularly C6-8 and in males,
   •   Recalcitrant skin, Recurrent invasive infections with pyogenic
       bacteria; Staph, pneumococci; SLE
       1.   Defects in proximal complement components

       Complement Deficiency Evaluation

€ Screening Tests
  •   CH - genetic deficiency except for C9 <10%, C9 -60%
  •   In males also do AH - alternative pathway - properdin
  •   Individual components to define specific defect

                 Complement Regulation

€ Membrane regulatory proteins inhibit activation of complement at the
   surface of normal host cells - CR1, DAF, C8bp, CD59
€ Inhibitory serum components act to attenuate activation of complement
   -Cl inhibitor - acting at C1; C4bp, Factors H and I - acting to block C3


€ Macrophages - resident phagocyte in most tissues; originate from
€ Neutrophils - critical line of defense against invading bacteria and fungi
€ Eosinophils are likely important in defense against metazoans

                     Neurophil Reserves

€ One-half of circulating neutrophils are marginated, can be rapidly
€ Bone marrow storage pool of mature neutrophils, bands and metas can
   be rapidly released by cytokines and corticosteroids
   •   Release leads to "left shift"
   •   Immature forms are somewhat less functional
€ Neonate, especially the premature, have a limited storage pool

       Neutrophil- Adherence and Chemiotaxis

€ Initial step in response to infection is adhesion to activated vascular
   endothelium via B2 integrins, selectins
€ Chemotaxis - directed migration of leukocytes towards higher concentra-
   tions of chemotactic factors
   •    Chemotactic factors include bacterial products and host derived
        lipid (leukotrienes, PAF) and protein (chemokine) products

       Neutrophil - Phagocytosis and Killing

€ Microbes are bound to neutrophils predominantly through receptor for
   opsonins - collectins, IgG, C3b and C3bi
€ IgG Recep (FcR) and Compl. Recep engaged particles are efficiently
   ingested and also trigger microbicidal mechanisms
   •   Respiratory burst -oxygen dependent
   •   Degranulation - myeloperoxidase; Defensins

                  Phagocyte Deficiency

€ Numeric
   •   Iatrogenic, autoimmune, genetic -G-CSFR mutation
€ Leukocyte adhesion deficiency
   •   Recurrent mucocutaneous and invasive tissue infections (non-
       bacteremic) due to all bacterial pathogens; delayed cord separa-
   •   Type I - absence of CD18 B2 integrins) -Diagnosis - suspect -
       persistent neutrophilia, confirm - flow cytometry for CD18, Mac-I,
   •   Type 2 - rare

          Chronic Granulomatous Disease

€ Invasive infections due to catalase positive bacteria and fungi;
   lymphadenopathy, hepatosplenomegaly, eczema and diarrhea
€ Age of onset typically first 6 months but may be much later
€ X-linked and autosomal dominant deficiency of phagocyte oxidase
€ Evaluation - NBT test for superoxide or FACS assay for H202
€ Therapy - prophylactic interferon ( and/or TMP/SMX, itraconazole

            Severe/unusual Infections with
       Intracellular/Cell-associated Microbes

€ T cell/Combined immunodeficiency
€ Infections with
   •    Viruses - particularly herpes group
   •    Intracellular bacteria, e.g., Mycobacteria, Listeria
   •    Protozoans- Pneumochysis, Toxoplasma, Cryptosporidium, Giardia
   •    Fungi -Cryptococcus, Histo, Cocci
   •    Mucocutaneous Candidiasis
€ Antibody production to newly encountered microbes also is compro-

   T Cell Recognition and Effector Function

€ T cells recognize short peptides bound to self HLA molecules
€ CD4 (helper) T cells
   •   Recognize peptides bound to HLA-D molecules (class II MHC) on
       specialized antigen presenting cells (e.g., macrophages, B cells)
€ CD8 (cytotoxic) T cells
   •   Recognize peptides bound to HLA-A, B, C (class I MHC) which are
       found on nearly all cells

   Mediators of CD4 (Helper) T Cell Function

€ Cytokines and cell surface ligands play a major role in helper function
€ B cell responses to protein antigens and the class of antibody produced
   are dependent on T cell contact via CD40 ligand and cytokines, e.g., IL-4
   = IgE, interferon-( = IgG
€ Loss of T cell help requite in combined cellular end humoral immunode-
   ficiency, even if B cells are normal

  Interleukins/lymphokines in Host Defense

€ TH1      lymphokines    -   IL-2,   IFN~,    end    TNF     -   activate
   macrophages/enhance defense vs intracellular pathogens
   •    Viruses, protozoa (Pneumocystis, Toxoplasma, Crypto), mycobac-
€ TH2 lymphokines - IL-4, IL-5, IL-'10 enhance IgE production, eosinophils
   these mediate allergy and may protect against mucosal infection with

  Macrophage Attraction and Activation by T

€ T cells and Macs secrete chemokines to attract each other to sites of
€ Macrophages are activated by cytokines secreted by T cells - interferon-
   ( GM-CSF and TNF, or by CD40 ligand
€ Activated macrophages have increased capacity to kill microbes -e.g.,
   mycobacteria, Toxoplasma - via enhanced oxygen radical, nitric oxide
   and other cidal substances

       Severe Combined Immunodeficiency

€ Presentation usually <6-12 months of age
€ Opportunistic infections and recurrent pyogenic infections
€ Chronic diarrhea, FTT, eczema
€ Common forms
   •   X-inked
   •   ADA deficiency
   •   Autosomal recessive
   •   Variants

                  DiGeorge Syndrome

€ DiGeorge: Developmental Array Defect
  •   Cardiac/great vessel >parathyroid >substantive thymic defect
  •   Characteristic facies: mandibular hypoplasia, hypertelorism
  •   Microdeletion Chromosome 22


€ Ataxia-Telangiectasia: Mutation in protein required for DNA repair
   •   Ataxia, ocular telangiectasia
   •   Recurrent sinopulmonary infections: variable IgA, IgG2, IgG4 and
       T cell deficit
   •   Malignancy in patients and carriers

          Initial Evaluation for Suspected
       T Cell/combined Immunodeficiency

€ Lymphocyte Count
€ DTH skin testing - Candida, Mumps, Tet/Dip
   •   Unreliable in <1-2 years of age -placement and reading by trained
   •   HIV testing
   •   Chest radiograph - thymus

 Assessment of CMI/T Cell Numbers and Func-
                            tion in Vitro

€ Indicated if DTH tests are negative and/or child <2 yr
€ Enumeration of T cell subsets, NK and B cells by flow cytometry using
   2-color FACS and standard procedures - must use age related norms
€ General T cell function - proliferation to mitogens (e.g., PHA) and/or
   antigens (e.g., candida, tetanus). This primarily measures a CD4

      Normal Age-adjusted T Cell Subsets

          1-6m      7-12m       13-24m    25-74m    Adult

CD4 to-   3211      3128        2601      1668      1027

5-95%     1153-     739-        505-      505-      500-1800
          5285      4463        2831      2831

CD4/CD    2.2       2.1         2.0       1.4       1.7

5-95%     0.9-3.5   0.8-3.4     0.6-3.4   0.7-2.1   0.4-3.0

Management of Combined Immunodeficiency

€ Bone-marrow transplant
€ Temporizing - IVIG, TMP-SMZ, aggressive treatment of infections,


€ Common things are common
€ Staged evaluation is indicated unless there is evidence of unusual or
   invasive infections or FTT
€ Isolated deficits in antibody mediated immunity rarely present before 6-9

   months of age

          Mediators of Acute Inflammation

€ Recruitment of circulating neutrophils to sites of inflammation involves
   sequential production of complement (C5a) and lipid mediators plat activ
   factor, leukotriene;), followed by cytokines - IL-1, TNF and chemokines -
€ These induce adhesins (selectins, ICAMs) on vascular endothelium,
   activate neutrophil ligands for these adhesins (e.g,. Integrins) and
   stimulate chemotaxis

   Pharmacologic Inhibitors of Inflammation

€ Cyclo-oxygenase inhibitors - e.g., NSAIDs, aspirin, indomethacin - act
   by blocking the production of prostaglandins
   •   Indicated in the treatment of Kawasaki, ARF
   •   Theoretically could shunt precursors into the leukotriene pathway
€ Pentoxifylline - phosphodiesterase inhibitor
   •   May diminish the inflammatory response in part by inhibiting
       production of TNF, IL-1
€ Thalidomide - reduces TNF production
   -leprosy (ENL), wasting in Tb/HIV?

   Pharmacologic Inhibitors of Inflammation

€ Corticosteroids are the most potent, broad
€ Inhibit production of lipid mediators (PAF, Leukotrienes) and pro-
   inflammatory cytokines (TNF, I/-1, chemokines)
€ Inhibits CMI/T cell function, e.g., production of IL-2, IFN-(
€ Evidence favors use in early H influenzae meningitis, selected patients
   with TB pericarditis or severe PCP, typhoid fever, airway obstruction in
   croup& inf. mono

 Antagonism of Pro-inflammatory Cytokines

€ IL-1 receptor antagonist, soluble IL-I and TNF receptors, IL-10,
   monoclonal antibodies to IL-1, TNF
   •   Antagonize LPS/infection induced sepsis syndrome in animal
       models disappointing in human trials to date
€ Antibodies to LPS disappointing to date in sepsis syndrome

            Hematopoietic Growth Factors

€ G-CSF - useful in neutropenia of nearly all causes, including chemother-
   apy induced congenital neutropenia, cyclic neutropenia, possibly
   neonatal sepsis
€ GM-CSF -generally less useful due to potency, side effects, and broader


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